Substituted pyrazole compounds as crac modulators

ABSTRACT

The present invention relates to compounds described herein Formula (I) and pharmaceutical acceptable salts thereof, which modulate the activity of calcium release-activated calcium (CRAC) channel. The invention also describes the compounds of Formula (I) and pharmaceutical compositions containing such compounds thereof for treating, managing, and/or lessening the severity of diseases, disorders, syndromes or conditions associated with the modulation of calcium release-activated calcium (CRAC) channel.

RELATED APPLICATIONS

The present application claims the benefit of priority to IndianProvisional Patent Application No. 0006/KOL/2012, filed on May 2, 2012and 1474/KOL/2012, filed on Dec. 28, 2012. The entire provisionalspecifications are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The invention relates to substituted pyrazole compounds,pharmaceutically acceptable salts thereof and pharmaceuticalcompositions for the treatment, management, and/or lessening of severityof diseases, disorders, syndromes or conditions associated with themodulation of calcium release-activated calcium (CRAC) channel. Theinvention also relates to methods of treating, managing and/or lesseningthe severity of the diseases disorders, syndromes or conditionsassociated with the modulation of CRAC. The invention also relates toprocesses for the preparation of the compounds of the invention.

BACKGROUND OF THE INVENTION

Inflammation is the response by the body to infection, irritation orinjury; wherein the immune cells of the body are activated in responseto any of these stimuli. Inflammation plays a key role in many diseasesnot only of the immune cells such as allergy, asthma, arthritis,dermatitis, multiple sclerosis, systemic lupus but also organtransplant, diabetes, cardiovascular disease, Alzheimer's disease,Parkinson's disease, inflammatory and/or irritable bowel syndrome (DiSabatino et. al., J. Immunol., 183, 3454-3462, 2009), psoriasis, andcancer. An initial inflammatory response to pathogens or injury isnecessary and required to fight infection or heal the wound, butsustained or persistent inflammation can lead to any of the chronicdisorders; characterized by the production of inflammatory cytokines as,specified above.

Inflammation is characterized by the production of different cytokinessuch as IL-2, IL-4, IL-10. IL-13, IL-17, IL-21, IL-23, IL-28, IFN-γ,TNF-α, etc., that have been implicated in playing a role in differentdiseases. Any drug which can modulate the production of these cytokineswould help alleviate the disease symptoms and may also cure it.

Ca⁺² signals have been shown to be essential for diverse cellularfunctions in different cell types including differentiation, effectorfunctions, and gene transcription in cells of the immune system as wellas regulating the cytokine signaling pathway through calcineurin andnuclear factor of activated T cells (NFAT).

In immune cells, sustained Ca⁺² influx has been shown to be necessaryfor complete and long-lasting activation of calcineurin-NFAT pathways,essential for cytokine production. Engagement of receptors such asT-cell antigen receptor (TCR), the B-cell antigen receptor (BCR), andthe Fc receptors (FcR) on mast cells, macrophages, and NK cells, leadsto the tyrosine phosphorylation and activation of phospholipase C-γ(PLC-γ). PLC-γ hydrolyzes phosphatidylinositol-3,4-biphosphate (PIP₂) tothe second messengers, inositol-1,4,5-triphosphate (IP₃) anddiacylglycerol (DAG). IP₃ binds to IP₃ receptors (IP₃R) in the membraneof the endoplasmic reticulum (ER) and induces the release of ER Ca⁺²stores into the cytoplasma. The decrease in the Ca⁺² concentration inthe ER induces store-operated Ca⁺² entry (SOCE) through plasma membraneCa⁺² channels. SOCE through highly Ca⁺²— selective Ca⁺²release-activated Ca⁺² (hereinafter, CRAC) channels constitutes themajor pathway of intracellular Ca⁺² entry in T cells, B cells,macrophages, mast cells, and other cell types (Parekh and Putney,Physiol. Rev., 85, 757-810, 2005).

The CRAC channel is comprised of two family proteins, one whichfunctions in sensing Ca⁺² levels in the ER—the stromal interactingmolecules (STIM)-1 and -2 and the other which is a pore-formingprotein—Orai1, 2 and 3. The STIM proteins are single transmembraneproteins localized on the ER membrane with their N-termini orientedtoward the lumen and containing an EF-hand Ca⁺² binding motif. Depletionof Ca⁺² from the ER causes Ca⁺² to dissociate from STIM, which causes aconformational change that promotes oligomerization and migration ofSTIM molecules to closely apposed ER-plasma membrane junctions. At thejunctions, the STIM oligomers interact with the Orai proteins. Inresting cells, Orai channels are dispersed across the plasma membraneand on depletion of Ca⁺² from the stores, they aggregate in the vicinityof the STIM punctae. The eventual increase in intracellular Ca⁺²concentration activates the calcineurin-NFAT pathway. NFAT activatestranscription of several genes including cytokine genes such as IL-2,etc along with other transcription factors such as AP-1, NFκB and Foxp3(Fahmer et. al., Immuno. Rev., 231, 99-112, 2009).

The role of CRAC channel in different diseases such as allergy,inflammatory bowel disease, thrombosis and breast cancer has beenreported in literature (Parekh, Nat. Rev., 9, 399-410, 2010). It hasbeen reported in the art that STIM1 and Orai1 are essential in in vitrotumor cell migration and in vivo tumor metastasis. Thus the involvementof store operated Ca²⁺ entry in tumor metastasis renders STIM1 and Orai1proteins potential targets for cancer therapy (Yang et.al., Cancer Cell,15, 124-134, 2009). Additional literature available on the involvementof CRAC channel in cancer are Abeele et. al., Cancer Cell, 1, 169-179,2002, Motiani et al., J. Biol. Chem., 285; 25, 19173-19183, 2010.

Recent literature reports the role of STIM1 and Orai1 in collagendependent arterial thrombosis in mice in vivo and that deficiency ineither protects against collagen dependent arterial thrombus formationas well as brain infarction (Varga-Szabo et. al., J. Exp. Med., 205,1583-1591, 2008; Braun et. al., Blood, 113, 2056-2063, 2009). The roleof STIM1-Orai1 mediated SOCE in thrombus formation makes Orai1 apotential target for treatment of thrombosis and related conditions(Gillo et. al., JBC, 285; 31, 23629-23638, 2010).

As the Orai pore channel proteins have been shown to be essential fortransmitting the signal induced by the binding of antigens to thecellular receptors on the immune cells, a potential Orai channelinteracting drug would be able to modulate the signaling therebyimpacting the secretion of the cytokines involved in, as mentionedhereinbefore, inflammatory conditions, cancer, allergic disorders,immune disorders, rheumatoid arthritis, cardiovascular diseases,thrombocytopathies, arterial and/or venous thrombosis and associated orrelated conditions which can be benefitted by the CRAC channelmodulatory properties of the compounds described herein.

Several compounds have been reported in the art as CRAC channelmodulators. For example, patent application publications WO2005009539,WO2005009954, WO2006081391, WO2006081389, WO2006034402, WO2006083477,WO2007087441, WO2007087442, WO2007087429, WO2007089904, WO2009017819,WO2009076454, WO2009035818, US20100152241, WO2010039238, WO2010025295,WO2010027875, WO2011034962, WO2012151355, WO2013059666, WO2013059677disclose the compounds for modulating CRAC channels.

SUMMARY OF THE INVENTION

In accordance with one aspect, the invention provides the compounds ofFormula (I):

wherein,

-   -   one of A and B is N and the other is CR₃;    -   L is selected from —C(O)NR₁₁—, —CR_(a)R_(b)NR₁₁— and        —NR₁₁CR_(a)R_(b)—;    -   at each occurrence, R_(a) and R_(b) are independently hydrogen,        substituted or unsubstituted alkyl or halogen;    -   ring E is 5 membered non aromatic heterocyclic ring selected        from Formula (a) to (c)

-   -   at each occurrence, X is selected from —C(O)—, —CR₄R₅— and —NR—;    -   at each occurrence, Y is —C(O)— or —CR₄R₅—;    -   provided that both of X and Y are not simultaneously —C(O)—;    -   R is selected from substituted or unsubstituted alkyl,        substituted or unsubstituted haloalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        heterocyclyl, —C(O)NR₆R₇, —C(O)OR₉ and —C(O)R₈;    -   R₁, which may be same or different at each occurrence, is        independently selected from halogen, cyano, nitro, hydroxyl,        substituted or unsubstituted alkyl, substituted or unsubstituted        haloalkyl, substituted or unsubstituted alkoxy, substituted or        unsubstituted haloalkoxy, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted cycloalkoxy, —NR₆R₇,        —NHC(O)R₈, and —C(O)OR₉; or any two of adjacent R₁ groups        together with the phenyl to which they are attached form        substituted or unsubstituted naphthalene ring;    -   R₂ is selected from halogen, cyano, nitro, hydroxyl, substituted        or unsubstituted alkyl, substituted or unsubstituted haloalkyl,        substituted or unsubstituted alkoxy, substituted or        unsubstituted haloalkoxy, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted cycloalkoxy, —NR₆R₇,        —NHC(O)R₈, and —C(O)OR₉;    -   R₃ is selected from hydrogen, halogen, cyano, nitro, hydroxyl,        substituted or unsubstituted alkyl, substituted or unsubstituted        haloalkyl, substituted or unsubstituted alkoxy, substituted or        unsubstituted haloalkoxy, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted cycloalkoxy, —NR₆R₇,        —NHC(O)R₈, and —C(O)OR₉;    -   R₄ and R₅, which may be same or different at each occurrence,        are independently selected from hydrogen, halogen, —OR₁₀,        substituted or unsubstituted alkyl, substituted or unsubstituted        haloalkyl, substituted or unsubstituted hydroxyalkyl, —C(O)OR₉,        —C(O)—NR₆R₇, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted aryl, substituted or unsubstituted        heteroaryl and substituted or unsubstituted heterocyclyl;        provided that, when any of R₄ or R₅ in Y is —OR₁₀ then R₁₀ is        not hydrogen;    -   R₆ and R₇, which may be same or different at each occurrence,        are independently selected from hydrogen, substituted or        unsubstituted alkyl and substituted or unsubstituted cycloalkyl;        or R₆ and R₇, together with the nitrogen atom to which they are        attached, may form a substituted or unsubstituted, saturated or        unsaturated 3 to 12 membered cyclic ring, wherein the        unsaturated cyclic ring may have one or two double bonds;    -   R₈, which may be same or different at each occurrence, is        independently selected from substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted cycloalkyl, and substituted or unsubstituted aryl;    -   R₉, which may be same or different at each occurrence, is        independently selected from hydrogen, substituted or        unsubstituted alkyl and substituted or unsubstituted aryl;    -   R₁₀ is selected from hydrogen, substituted or unsubstituted        alkyl, substituted or unsubstituted cycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl and        substituted or unsubstituted heterocyclyl;    -   at each occurrence, R₁₁ is independently hydrogen or substituted        or unsubstituted alkyl; and    -   n is an integer ranging from 0 to 4, both inclusive;    -   or a pharmaceutically acceptable salt thereof.    -   According to one embodiment, there are provided compounds having        the Formula (II):

-   -   or a pharmaceutically acceptable salt thereof;    -   wherein ring E, R₁, R₂, R₃, L and ‘n’ are as defined herein        above.    -   According to another embodiment, there are provided compounds        having Formula (III):

-   -   or a pharmaceutically acceptable salt thereof;    -   wherein ring E, R₁, R₂, R₃, L and ‘n’ are as defined herein        above.

It should be understood that the Formula (I), Formula (II) and Formula(III) structurally encompasses all tautomers, stereoisomers, enantiomersand diastereomers, including isotopes wherever applicable andpharmaceutically acceptable salts that may be contemplated from thechemical structure of the genera described herein.

The details of one or more embodiments of the invention set forth in thebelow are illustrative in nature only and not intended to limit to thescope of the invention. Other features, objects and advantages of theinventions will be apparent from the description and claims.

-   -   According to one embodiment there are provided a compound of        Formula (I) wherein ring

is selected from Formula (i) to (iv)

-   -   where R, R₄, R₅ and R₁₀ are as defined herein above.    -   According to another embodiment there are provided a compound of        Formula (I) wherein ring

is selected from Formula (v) to (vii)

-   -   where R, R₄, and R₅ are as defined herein above.    -   According to one embodiment there are provided a compound of        Formula (I) wherein ring

is selected from Formula (viii) to (x)

-   -   where R, R₄, and R₅ are as defined herein above.

According to another embodiment are provided compounds of Formula (I),(II) and/or (III) in which L is selected from —C(O)NR₁₁—, —NR₁₁C(O)— and—NR₁₁CR_(a)R_(b)— wherein R₁₁, R_(a) and R_(b) are independently ahydrogen or substituted or unsubstituted alkyl.

According to another embodiment are provided compounds of Formula (I),(II) and/or (III) in which R₁ is same or different and are independentlyselected from halogen, cyano, nitro, hydroxyl, substituted orunsubstituted alkyl, substituted or unsubstituted haloalkyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted haloalkoxy andsubstituted or unsubstituted cycloalkyl; and ‘n’ is 0, 1, 2, or 3.

According to another embodiment are provided compounds of Formula (I),(II) and/or (III) in which R₂ is selected from halogen, hydroxyl, cyano,nitro, substituted or unsubstituted alkyl, substituted or unsubstitutedhaloalkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted haloalkoxy and substituted or unsubstituted cycloalkyl.

According to another embodiment are provided compounds of Formula (I),(II) and/or (III) in which R₃ is selected from hydrogen, halogen, cyano,nitro, hydroxyl, substituted or unsubstituted alkyl, substituted orunsubstituted haloalkyl, substituted or unsubstituted alkoxy andsubstituted or unsubstituted cycloalkyl.

According to another embodiment are provided compounds of Formula (I) inwhich one of A and B is N and the other is CH; L is —C(O)NH—, —NHC(O)—or —NHCH₂—; R₁ is same or different and are independently selected fromhalogen, substituted or unsubstituted alkyl, substituted orunsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; ‘n’is 0, 1, 2, or 3; R₂ is halogen, substituted or unsubstituted alkyl,substituted or unsubstituted haloalkyl or substituted or unsubstitutedcycloalkyl; R₃ is selected from hydrogen, halogen or substituted orunsubstituted alkyl; and ring E is selected from

In another aspect, the invention provides a pharmaceutical compositioncomprising at least one compound of Formula (I) and at least onepharmaceutically acceptable excipient.

In another aspect of the invention, there is provided a compound ofFormula (I) useful in treating, managing and/or lessening the severityof the diseases, disorders, syndromes or conditions associated with themodulation of CRAC channel.

In another aspect, the invention provides a pharmaceutical compositionof a compound of Formula (I) useful in treating, managing and/orlessening the severity of the diseases disorders, syndromes orconditions associated with the modulation of CRAC channel in a subjectin need thereof by administering to the subject, one or more compoundsdescribed herein in an amount.

In another aspect, the invention provides a method of modulating ionchannel activity, for example, CRAC channel, by administering effectiveamount of a compound of Formula (I) and/or pharmaceutically acceptablesalts.

In another aspect, the invention provides a method of modulating thesecretion of cytokines, for example IL-2, IL-4, IL-10, IL-13, IL-17,IL-21, IL-23, IL-28, IFN-γ and TNF-α and the like, by regulating thecytokine signalling pathway through calcineurin and NFAT cells.

In another aspect, there are provided processes for the preparation ofcompounds of Formula (IIa):

-   -   wherein L is —NR₁₁C(O)— or NR₁₁CR_(a)R_(b);    -   ring E, A, B, R_(a), R_(b), R₁, R₂, R₃, R₁₁ and ‘n’ are as        described herein above;        the process comprising the steps:    -   a) oxidizing a compound of Formula (10) where X′ is halogen,        NO₂, COOR′ where R′ is H, alkyl etc., by using suitable        oxidation agents to give compound of Formula (11) in suitable        solvent(s);

-   -   b) converting a acid compound of Formula (11) to cyclized        compound of compound of Formula (12) by following acid ester        formation then heterocyclic ring formation using hydrazine        hydrate followed by triphosgene

-   -   c) coupling of compound Formula (12) where X′ is halogen, with        compound of Formula (6) where L′ is C(O) or CR_(a)R_(b) where        R_(a), R_(b) and R₁₁ are hydrogen or alkyl, to give compound of        Formula (IIa) by using suitable reagents and suitable solvent.

In another aspect, there are provided processes for the preparation ofcompounds of Formula (IIb):

-   -   wherein ring E, A, B, R₁, R₂, R₃, R₁₁ and ‘n’ are as described        herein above;        amide coupling of compound Formula (12) where X′ is COOR′ where        R′ is H, alkyl etc., with compound of Formula (5a) to give        compound of Formula (IIb) by using suitable amide coupling        methods

In another aspect, there are provided processes for the preparation ofcompounds of Formula (IIa):

-   -   wherein L is —NR₁₁C(O)— or NR₁₁CR_(a)R_(b);    -   ring E, A, B, R_(a), R_(b), R₁, R₂, R₃, R₁₁ and ‘n’ are as        described herein above;    -   the process comprising the steps:    -   a) reducing a nitro group in compound of Formula (12) where X′        is NO₂, by using suitable reducing agent to give amino compound        of Formula (13) where R₁₁ is hydrogen, in suitable solvent

-   -   b) coupling of compound of Formula (13) with compound of        Formula (8) by using suitable amide coupling reagents or        suitable reductive amidation reagents to give compound of        Formula (IIa)

DETAILED DESCRIPTION OF THE INVENTION Definitions and Abbreviations

Unless otherwise stated, the following terms used in the specificationand claims have the meanings given below.

For purposes of interpreting the specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

The terms “halogen” or “halo” means fluorine, chlorine, bromine, oriodine.

Unless otherwise stated, in the present application “oxo” means C(═O)group. Such an oxo group may be a part of either a cycle or a chain inthe compounds of the present invention.

The term “alkyl” refers to an alkane derived hydrocarbon radical thatincludes solely carbon and hydrogen atoms in the backbone, contains nounsaturation, has from one to six carbon atoms, and is attached to theremainder of the molecule by a single bond, e.g., methyl, ethyl,n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl) and the like. Unless set forth or recited tothe contrary, all alkyl groups described or claimed herein may bestraight chain or branched, substituted or unsubstituted.

The term “alkenyl” refers to a hydrocarbon radical containing from 2 to10 carbon atoms and including at least one carbon-carbon double bond.Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl,2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl and the like. Unless set forth or recited to the contrary, allalkenyl groups described or claimed herein may be straight chain orbranched, substituted or unsubstituted.

The term “alkynyl” refers to a hydrocarbon radical containing 2 to 10carbon atoms and including at least one carbon-carbon triple bond.Non-limiting examples of alkynyl groups include ethynyl, propynyl,butynyl and the like. Unless set forth or recited to the contrary, allalkynyl groups described or claimed herein may be straight chain orbranched, substituted or unsubstituted.

The term “alkoxy” refers to an alkyl group attached via an oxygenlinkage. Non-limiting examples of such groups are methoxy, ethoxy andpropoxy and the like. Unless set forth or recited to the contrary, allalkoxy groups described or claimed herein may be straight chain orbranched, substituted or unsubstituted.

The term “alkenyloxy” refers to an alkenyl group attached via an oxygenlinkage. Non-limiting examples of such groups are vinyloxy, allyloxy,1-butenyloxy, 2-butenyloxy, isobutenyloxy, 1-pentenyloxy, 2-pentenyloxy,3-methyl-1-butenyloxy, 1-methyl-2-butenyloxy, 2,3-dimethylbutenyloxy,1-hexenyloxy and the like. Unless set forth or recited to the contrary,all alkenyloxy groups described or claimed herein may be straight chainor branched, substituted or unsubstituted.

The term “alkynyloxy” refers to an alkynyl group attached via an oxygenlinkage. Non-limiting examples of such groups are acetylenyloxy,propynyloxy, 1-butynyloxy, 2-butynyloxy, 1-pentynyloxy, 2-pentynyloxy,3-methyl-1-butynyloxy, 1-hexynyloxy, 2-hexynyloxy, and the like. Unlessset forth or recited to the contrary, all alkynyloxy groups described orclaimed herein may be straight chain or branched, substituted orunsubstituted.

The term “cycloalkyl” refers to a non-aromatic mono or multicyclic ringsystem having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like. Examples of multicyclic cycloalkylgroups include, but are not limited to, perhydronapththyl, adamantyl andnorbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g.,spiro(4,4)non-2-yl and the like. Unless set forth or recited to thecontrary, all cycloalkyl groups described or claimed herein may besubstituted or unsubstituted.

The term “cycloalkoxy” refers to an cycloalkyl, defined herein, groupattached via an oxygen linkage. Non-limiting examples of such groups arecyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy and the like.Unless set forth or recited to the contrary, all alkoxy groups describedor claimed herein may be straight chain or branched, substituted orunsubstituted.

The term “cycloalkenyl” refers to a non-aromatic mono or multicyclicring system having 3 to 12 carbon atoms and including at least onecarbon-carbon double bond, such as cyclopentenyl, cyclohexenyl,cycloheptenyl and the like. Unless set forth or recited to the contrary,all cycloalkenyl groups described or claimed herein may be substitutedor unsubstituted.

The term “cycloalkylalkyl” refers to a cycloalkyl group as definedabove, directly bonded to an alkyl group as defined above, e.g.,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cyclohexylethyl, etc. Unless set forth or recited tothe contrary, all cycloalkylalkyl groups described or claimed herein maybe substituted or unsubstituted.

The term “haloalkyl” refers to an alkyl group as defined above that issubstituted by one or more halogen atoms as defined above. Preferably,the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkylincluding perhaloalkyl. A monohaloalkyl can have one iodine, bromine,chlorine or fluorine atom. Dihaloalkyl and polyhaloalkyl groups can besubstituted with two or more of the same halogen atoms or a combinationof different halogen atoms. Preferably, a polyhaloalkyl is substitutedwith up to 12 halogen atoms. Non-limiting examples of a haloalkylinclude fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl, dichloropropyl and the like. Aperhaloalkyl refers to an alkyl having all hydrogen atoms replaced withhalogen atoms.

The term “haloalkoxy” refers to an haloalkyl, defined herein, groupattached via an oxygen linkage. Non-limiting examples of such groups aremonohaloalkoxy, dihaloalkoxy or polyhaloalkoxy including perhaloalkoxy.Unless set forth or recited to the contrary, all haloalkoxy groupsdescribed or claimed herein may be straight chain or branched,substituted or unsubstituted.

The term “hydroxyalkyl” refers to an alkyl group, as defined above thatis substituted by one or more hydroxy groups. Preferably, thehydroxyalkyl is monohydroxyalkyl or dihydroxyalkyl. Non-limitingexamples of a hydroxyalkyl include 2-hydroxyethyl, 3-hydroxypropyl,2-hydroxypropyl, and the like.

The term “aryl” refers to an aromatic radical having 6- to 14-carbonatoms, including monocyclic, bicyclic and tricyclic aromatic systems,such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl andthe like. Unless set forth or recited to the contrary, all aryl groupsdescribed or claimed herein may be substituted or unsubstituted.

The term “arylalkyl” refers to an aryl group as defined above directlybonded to an alkyl group as defined above, e.g., —CH₂C₆H₅ and —C₂H₄C₆H₅.Unless set forth or recited to the contrary, all arylalkyl groupsdescribed or claimed herein may be substituted or unsubstituted.

A “3-12 membered cyclic ring” as used herein refers to a monocyclic,bicyclic, polycyclic heteroaryl or heterocyclic ring systems. Theaseheteroaryl or heterocyclic ring as described herein.

The term “heterocyclic ring” or “heterocyclyl ring” or “heterocyclyl”,unless otherwise specified, refers to substituted or unsubstitutednon-aromatic 3- to 15-membered ring which consists of carbon atoms andwith one or more heteroatom(s) independently selected from N, O or S.The heterocyclic ring may be a mono-, bi- or tricyclic ring system,which may include fused, bridged or spiro ring systems and the nitrogen,carbon, oxygen or sulfur atoms in the heterocyclic ring may beoptionally oxidized to various oxidation states. In addition, thenitrogen atom may be optionally quaternized, the heterocyclic ring orheterocyclyl may optionally contain one or more olefinic bond(s), andone or two carbon atoms(s) in the heterocyclic ring or heterocyclyl maybe interrupted with —CF₂—, —C(O)—, —S(O)—, S(O)₂, —C(═N-alkyl)-, or—C(═N-cycloalkyl), etc. In addition heterocyclic ring may also be fusedwith aromatic ring. Non-limiting examples of heterocyclic rings includeazetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indanyl,indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl,octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl,pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl,tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl,thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone indoline, benzodioxole, tetrahydroquinoline,tetrahydrobenzopyran and the like. The heterocyclic ring may be attachedby any atom of the heterocyclic ring that results in the creation of astable structure. Unless set forth or recited to the contrary, allheterocyclyl groups described or claimed herein may be substituted orunsubstituted; substituents may be on same or different ring atom.

The term “heteroaryl” unless otherwise specified, refers to asubstituted or unsubstituted 5- to 14-membered aromatic heterocyclicring with one or more heteroatom(s) independently selected from N, O orS. The heteroaryl may be a mono-, bi- or tricyclic ring system. Theheteroaryl ring may be attached by any atom of the heteroaryl ring thatresults in the creation of a stable structure. Non-limiting examples ofa heteroaryl ring include oxazolyl, isoxazolyl, imidazolyl, furyl,indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl,thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl,benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl,cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl,isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl,phthalazinyl and the like. Unless set forth or recited to the contrary,all heteroaryl groups described or claimed herein may be substituted orunsubstituted.

The term “heterocyclylalkyl” refers to a heterocyclic ring radicaldirectly bonded to an alkyl group. The heterocyclylalkyl radical may beattached to the main structure at any carbon atom in the alkyl groupthat results in the creation of a stable structure. Unless set forth orrecited to the contrary, all heterocyclylalkyl groups described orclaimed herein may be substituted or unsubstituted.

The term “heteroarylalkyl” refers to a heteroaryl ring radical directlybonded to an alkyl group. The heteroarylalkyl radical may be attached tothe main structure at any carbon atom in the alkyl group that results inthe creation of a stable structure. Unless set forth or recited to thecontrary, all heteroarylalkyl groups described or claimed herein may besubstituted or unsubstituted.

Unless otherwise specified, the term “substituted” as used herein refersto a group or moiety having one or more substituents attached to thestructural skeleton of the group or moiety. Such substituents include,but are not limited to hydroxy, halogen, carboxyl, cyano, nitro, oxo(═O), thio (═S), alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclicring, heterocyclylalkyl, heteroarylalkyl, —C(O)OR^(x), —C(O)R^(x),—C(S)R^(x), —C(O)NR^(x)R^(y), —NR^(x)C(O)NR^(y)R^(z),—N(R^(x))S(O)R^(y), —N(R^(x))S(O)₂R^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y),—NR^(x)C(S)R^(y), —NR^(x)C(S)NR^(y)R^(z), —S(O)₂NR^(x)R^(y), —OR^(x),—OC(O)R^(x), —OC(O)NR^(x)R^(y), —R^(x)C(O)OR^(y), —R^(x)C(O)NR^(y)R^(z),—R^(x)C(O)R^(y), —SR^(x), and —S(O)₂R^(x); wherein each occurrence ofR^(x), R^(y) and R^(z) are independently selected from hydrogen,halogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic ring,heterocyclylalkyl and heteroarylalkyl. The aforementioned “substituted”groups cannot be further substituted. For example, when the substituenton “substituted alkyl” is “aryl” or “alkenyl”, the aryl or alkenylcannot be substituted aryl or substituted alkenyl, respectively.

The term “stereoisomer” refers to a compound made up of the same atomsbonded by the same bonds but having different three-dimensionalstructures which are not interchangeable. The three-dimensionalstructures are called configurations. As used herein, the term“enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. The term “chiral center”refers to a carbon atom to which four different groups are attached. Asused herein, the term “diastereomers” refers to stereoisomers which arenot enantiomers. The terms “racemate” or “racemic mixture” refer to amixture of equal parts of enantiomers.

A “Tautomer” refers to a compound that undergo rapid proton shifts fromone atom of the compound to another atom of the compound. Some of thecompounds described herein may exist as tautomers with different pointsof attachment of hydrogen. The individual tautomers as well as mixturethereof are encompassed with compounds of Formula (I).

The term “treating” or “treatment” of a state, disease, disorder,condition or syndrome includes: (a) delaying the appearance of clinicalsymptoms of the state, disease, disorder, condition or syndromedeveloping in a subject that may be afflicted with or predisposed to thestate, disease, disorder, condition or syndrome but does not yetexperience or display clinical or subclinical symptoms of the state,disease, disorder, condition or syndrome; (b) inhibiting the state,disease, disorder, condition or syndrome, i.e., arresting or reducingthe development of the disease or at least one clinical or subclinicalsymptom thereof; c) lessening the severity of a disease disorder orcondition or at least one of its clinical or subclinical symptomsthereof; and/or (d) relieving the disease, i.e., causing regression ofthe state, disorder or condition or at least one of its clinical orsubclinical symptoms.

The term “modulate” or “modulating” or “modulation” refers to a decreaseor inhibition in the amount, quality, or effect of a particularactivity, function or molecule; by way of illustration that block orinhibit calcium release-activated calcium (CRAC) channel. Any suchmodulation, whether it be partial or complete inhibition is sometimesreferred to herein as “blocking” and corresponding compounds as“blockers”. For example, the compounds of the invention are useful asmodulators of the CRAC channel.

The term “subject” includes mammals, preferably humans and otheranimals, such as domestic animals; e.g., household pets including catsand dogs.

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a subject for treating a disease, disorder,syndrome or condition, is sufficient to cause the effect in the subjectwhich is the purpose of the administration. The “therapeuticallyeffective amount” will vary depending on the compound, the disease andits severity and the age, weight, physical condition and responsivenessof the subject to be treated.

Unless otherwise stated, in the present application “protecting group”refers to the groups intended to protect an otherwise labile group,e.g., an amino group, a carboxy group and the like, under specificreaction conditions. Various protecting groups alongwith the methods ofprotection and deprotection are generally known to a person of ordinaryskilled in the art. Incorporated herein in this regard as reference isGreene's Protective Groups in Organic Synthesis, 4th Edition, John Wiley& Sons, New York. In the present invention, preferred amino protectinggroups are t-butoxycarbonyl, benzyloxycarbonyl, acetyl and the like;while preferred carboxy protecting groups are esters, amides and thelike.

Pharmaceutically Acceptable Salts:

The compounds of the invention may form salts with acid or base. Thecompounds of invention may be sufficiently basic or acidic to formstable nontoxic acid or base salts, administration of the compound as apharmaceutically acceptable salt may be appropriate. Non-limitingexamples of pharmaceutically acceptable salts are inorganic, organicacid addition salts formed by addition of acids including hydrochloridesalts. Non-limiting examples of pharmaceutically acceptable salts areinorganic, organic base addition salts formed by addition of bases. Thecompounds of the invention may also form salts with amino acids.Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion.

With respect to the overall compounds described by the Formula (I), theinvention extends to these stereoisomeric forms and to mixtures thereof.To the extent prior art teaches synthesis or separation of particularstereoisomers, the different stereoisomeric forms of the invention maybe separated from one another by a method known in the art, or a givenisomer may be obtained by stereospecific or asymmetric synthesis orchiral HPLC (high performance liquid chromatography. Tautomeric formsand mixtures of compounds described herein are also contemplated.

Pharmaceutical Compositions

The invention relates to pharmaceutical compositions containing thecompound of Formula (I). In particular, the pharmaceutical compositionscontain a therapeutically effective amount of at least one compound ofFormula (I) and at least one pharmaceutically acceptable excipient (suchas a carrier or diluent). Preferably, the pharmaceutical compositionsinclude the compound(s) described herein in an amount sufficient tomodulate the calcium release-activated calcium (CRAC) channel to treatCRAC channel mediated diseases such as inflammatory diseases, autoimmunediseases, allergic disorders, organ transplant, cancer andcardiovascular disorders when administered to a subject.

The compound of the invention may be incorporated with apharmaceutically acceptable excipient (such as a carrier or a diluent)or be diluted by a carrier, or enclosed within a carrier which can be inthe form of a capsule, sachet, paper or other container. Thepharmaceutically acceptable excipient includes a pharmaceutical agentthat does not itself induce the production of antibodies harmful to theindividual receiving the composition, and which may be administeredwithout undue toxicity.

Examples of suitable carriers include, but are not limited to, water,salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylatedcastor oil, peanut oil, olive oil, gelatin, lactose, terra alba,sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose,magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid orlower alkyl ethers of cellulose, silicylic acid, fatty acids, fatty acidamines, fatty acid monoglycerides and diglycerides, pentaerythritolfatty acid esters, polyoxyethylene, hydroxymethylcellulose andpolyvinylpyrrolidone.

The pharmaceutical composition may also include one or morepharmaceutically acceptable auxiliary agents, wetting agents,emulsifying agents, suspending agents, preserving agents, salts forinfluencing osmotic pressure, buffers, sweetening agents, flavoringagents, colorants, or any combination of the foregoing. Thepharmaceutical composition of the invention may be Formulated so as toprovide quick, sustained, or delayed release of the active ingredientafter administration to the subject by employing procedures known in theart.

The pharmaceutical compositions described herein may be prepared byconventional techniques known in the art. For example, the activecompound can be mixed with a carrier, or diluted by a carrier, orenclosed within a carrier, which may be in the form of an ampoule,capsule, sachet, paper, or other container. When the carrier serves as adiluent, it may be a solid, semi-solid, or liquid material that acts asa vehicle, excipient, or medium for the active compound. The activecompound can be adsorbed on a granular solid container, for example, ina sachet.

The pharmaceutical compositions may be administered in conventionalforms, for example, capsules, tablets, aerosols, solutions, suspensionsor products for topical application.

The route of administration may be any route which effectivelytransports the active compound of the invention to the appropriate ordesired site of action. Suitable routes of administration include, butare not limited to, oral, nasal, pulmonary, buccal, subdermal,intradermal, transdermal, parenteral, rectal, depot, subcutaneous,intravenous, intraurethral, intramuscular, intranasal, ophthalmic (suchas with an ophthalmic solution) or topical (such as with a topicalointment).

Solid oral Formulations include, but are not limited to, tablets,caplets, capsules (soft or hard gelatin), orally disintegrating tablets,dragees (containing the active ingredient in powder or pellet form),troches and lozenges. Tablets, dragees, or capsules having talc and/or acarbohydrate carrier or binder or the like are particularly suitable fororal application. Liquid Formulations include, but are not limited to,syrups, emulsions, suspensions, solutions, soft gelatin and sterileinjectable liquids, such as aqueous or non-aqueous liquid suspensions orsolutions. For parenteral application, particularly suitable areinjectable solutions or suspensions, preferably aqueous solutions withthe active compound dissolved in polyhydroxylated castor oil.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

For administration to human patients, the total daily dose of thecompounds of the invention depends, of course, on the mode ofadministration. For example, oral administration may require a highertotal daily dose, than an intravenous (direct into blood). The quantityof active component in a unit dose preparation may be varied or adjustedfrom 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, and mosttypically 10 mg to 500 mg, according to the potency of the activecomponent or mode of administration.

Suitable doses of the compounds for use in treating the diseasesdisorders, syndromes and conditions described herein can be determinedby those skilled in the relevant art. Therapeutic doses are generallyidentified through a dose ranging study in humans based on preliminaryevidence derived from the animal studies. Doses must be sufficient toresult in a desired therapeutic benefit without causing unwanted sideeffects for the patient. For example, the daily dosage of the CRACchannel modulator can range from about 0.1 to about 30.0 mg/kg. Mode ofadministration, dosage forms, suitable pharmaceutical excipients,diluents or carriers can also be well used and adjusted by those skilledin the art. All changes and modifications are envisioned within thescope of the invention.

Method of Treatment

In a further embodiment, the invention is directed to the treatment orprophylaxis of inflammatory conditions by administering an effectiveamount of a compound of the present invention.

Inflammation is part of the normal host response to infection and injuryor exposure to certain substances prone to cause it. Inflammation beginswith the immunologic process of elimination of invading pathogens andtoxins to repair damaged tissue. Hence, these responses are extremelyordered and controlled. However, excessive or inappropriate inflammationcontributes to a range of acute and chronic human diseases and ischaracterized by the production of inflammatory cytokines, arachidonicacid-derived eicosanoids (prostaglandins, thromboxanes, leukotrienes,and other oxidized derivatives), other inflammatory agents (e.g.,reactive oxygen species), and adhesion molecules. As used herein, theterm “inflammatory conditions” is defined as a disease or disorder orabnormality characterized by involvement of inflammatory pathwaysleading to inflammation, and which may result from, or be triggered by,a dysregulation of the normal immune response.

The compound(s) of the present invention are useful in treatment ofinflammatory conditions including, but not limited to, diseases of manybody systems such as (musculoskeletal) arthritis, myositis, rheumatoidarthritis, osteoarthritis, gout, gouty arthritis, acute pseudogout,Reiter's syndrome, ankylosing spondylitis, psoriatic arthritis,dermatomyositis; (pulmonary) pleuritis, pulmonary fibrosis or nodules,restrictive lung disease, chronic obstructive pulmonary disease (COPD),acute respiratory distress syndrome (ARDS), (cardiovascular) aorticvalve stenosis, restenosis, arrhythmias, coronary arteritis,myocarditis, pericarditis, Raynaud's phenomenon, systemic vasculitis,angiogenesis, atherosclerosis, ischaemic heart disease, thrombosis,myocardial infarction; (gastrointestinal) dysmotility, dysphagia,inflammatory bowel diseases, pancreatitis, (genitourinary) interstitialcystitis, renal tubular acidosis, urosepsis, (skin) purpura, vasculitisscleroderma, eczema, psoriasis, (neurologic) central nervous systemdisorders, cranial and peripheral neuropathies, peripheral neuropathy,radiculopathy, spinal cord or cauda equina compression with sensory andmotor loss, multiple sclerosis (MS) (mental) cognitive dysfunction,Alzheimer's disease, (neoplastic) lymphoma, inflammation associated withcancer, (ophthalmologic) iridocyclitis, keratoconjunctivitis sicca,uveitis, (hematologic) chronic anemia, thrombocytopenia, (renal)amyloidosis of the kidney, glomerulonephritis, kidney failure and otherdiseases such as tuberculosis, leprosy, sarcoidosis, syphilis, Sjögren'ssyndrome, cystitis, fibromyalgia, fibrosis, septic shock, endotoxicshock, surgical complications, systemic lupus erthymotosus (SLE),transplantation associated arteriopathy, graft vs. host reaction,allograft rejection, chronic transplant rejection.

The inflammatory bowel diseases also include Crohn's disease, ulcerativecolitis, indeterminate colitis, necrotizing enterocolitis, andinfectious colitis.

“Allergic disorders” is defined as disorders/diseases that are caused bya combination of genetic and environmental factors resulting in ahypersensitivity disorder of the immune system. Allergic diseases arecharacterized by excessive immunoglobulin E (IgE) production, mast celldegranulation, tissue eosinophilia and mucus hypersecretion, resultingin an extreme inflammatory response. These responses also take placeduring infection with multicellular parasites, and are linked to theproduction of a characteristic set of cytokines by T helper (Th) 2cells. For example asthma is a chronic inflammatory condition of thelungs, characterized by excessive responsiveness of the lungs tostimuli, in the form of infections, allergens, and environmentalirritants. Allergic reactions can also result from food, insect stings,and reactions to medications like aspirin and antibiotics such aspenicillin. Symptoms of food allergy include abdominal pain, bloating,vomiting, diarrhea, itchy skin, and swelling of the skin during hives.Food allergies rarely cause respiratory (asthmatic) reactions, orrhinitis. Insect stings, antibiotics, and certain medicines produce asystemic allergic response that is also called anaphylaxis. The maintherapeutic interest around CRAC in allergic disorders, originates fromits role in lymphocytes and mast cells, CRAC activation being arequirement for lymphocyte activation.

The compound(s) of the present invention are useful in treatment ofallergic disorders including, but not limited to, atopic dermatitis,atopic eczema, Hay fever, asthma, urticaria (including chronicidiopathic urticaria), vernal conjunctivitis, allergicrhinoconjunctivitis, allergic rhinitis (seasonal and perennial),sinusitis, otitis media, allergic bronchitis, allergic cough, allergicbronchopulmonary aspergillosis, anaphylaxis, drug reaction, foodallergies and reactions to the venom of stinging insects.

In yet another embodiment, the invention is directed to the treatment of“immune disorders” by administering an effective amount of a compound ofthe present invention.

The compounds of this invention can be used to treat subjects withimmune disorders. As used herein, the term “immune disorder” and liketerms mean a disease, disorder or condition caused by dysfunction ormalfunction of the immune system as a whole or any of its componentsincluding autoimmune disorders. Such disorders can be congenital oracquired and may be characterized by the component(s) of the immunesystem getting affected or by the immune system or its componentsgetting overactive. Immune disorders include those diseases, disordersor conditions seen in animals (including humans) that have an immunecomponent and those that arise substantially or entirely due to immunesystem-mediated mechanisms. In addition, other immune system mediateddiseases, such as graft-versus-host disease and allergic disorders, willbe included in the definition of immune disorders herein. Because anumber of immune disorders are caused by inflammation or lead toinflammation, there is some overlap between disorders that areconsidered immune disorders and inflammatory disorders. For the purposeof this invention, in the case of such an overlapping disorder, it maybe considered either an immune disorder or an inflammatory disorder. Anautoimmune disorder is a condition that occurs when the immune systemmistakenly attacks and destroys its own body cells, tissues and/ororgans. This may result in temporary or permanent destruction of one ormore types of body tissue, abnormal growth of an organ, changes in organfunction, etc. For example, there is destruction of insulin producingcells of the pancreas in Type 1 diabetes mellitus. Different autoimmunedisorders can target different tissues, organs or systems in an animalwhile some autoimmune disorders target different tissues, organs orsystems in different animals. For example, the autoimmune reaction isdirected against the gastrointestinal tract in Ulcerative colitis andthe nervous system in multiple sclerosis whereas in systemic lupuserythematosus (lupus), affected tissues and organs may vary amongindividuals with the same disease. For example, one person with lupusmay have affected skin and joints whereas another may have affectedkidney, skin and lungs.

Specific autoimmune disorders that may be ameliorated using thecompounds and methods of this invention include without limitation,autoimmune disorders of the skin (e.g., psoriasis, dermatitisherpetiformis, pemphigus vulgaris, and vitiligo), autoimmune disordersof the gastrointestinal system (e.g., Crohn's disease, ulcerativecolitis, primary biliary cirrhosis, and autoimmune hepatitis),autoimmune disorders of the endocrine glands (e.g., Type 1 orimmune-mediated diabetes mellitus, Grave's disease. Hashimoto'sthyroiditis, autoimmune oophoritis and orchitis, and autoimmune disorderof the adrenal gland), autoimmune disorders of multiple organs(including connective tissue and musculoskeletal system diseases) (e.g.,rheumatoid arthritis, systemic lupus erythematosus, scleroderma,polymyositis, dermatomyositis, spondyloarthropathies such as ankylosingspondylitis, and Sjogren's syndrome), autoimmune disorders of thenervous system (e.g., multiple sclerosis, myasthenia gravis, autoimmuneneuropathies such as Guillain-Barre, and autoimmune uveitis), autoimmunedisorders of the blood (e.g., autoimmune hemolytic anemia, perniciousanemia, and autoimmune thrombocytopenia) and autoimmune disorders of theblood vessels (e.g., temporal arteritis, anti-phospholipid syndrome,vasculitides such as Wegener's granulomatosis, and Behcet's disease).

“Treatment of an immune disorder” herein refers to administering acompound or a composition of the invention alone or in combination withother agents to a subject, who has an immune disorder, a sign or symptomof such a disease or a risk factor towards such a disease, with apurpose to cure, relieve, alter, affect, or prevent such disorder orsign or symptom of such a disease, or the predisposition towards it.

In another embodiment, the invention is directed to the treatment ofcancer by administering an effective amount of a compound of the presentinvention.

It has been reported in the art that STIM1 and Orai1 are essential in invitro tumor cell migration and in vivo tumor metastasis. Thus theinvolvement of store operated Ca²⁺ entry in tumor metastasis rendersSTIM1 and Orai1 proteins potential targets for cancer therapy (Yanget.al., Cancer Cell, 15, 124-134, 2009). Additional literature availableon the involvement of CRAC channel in cancer are Abeele et. al., CancerCell, 1, 169-179, 2002, Motiani et al., J. Biol. Chem., 285; 25,19173-19183, 2010.

The compound(s) of the present invention may be useful in treatment ofcancers and/or its metastasis including, but not limited to, breastcancer, lung cancer, pancreatic cancer, ovarian cancer, colon cancer,neck cancer, kidney cancer, bladder cancer, thyroid, blood cancer, skincancer and the like. In yet another embodiment, the invention isdirected to the treatment or prophylaxis of allergic disorders byadministering an effective amount of a compound of the presentinvention.

In yet another embodiment, the invention is directed to the treatment orprophylaxis of cardiovascular diseases or disorders by administering aneffective amount of a compound of the present invention.

The compounds of this invention can be used to treat subjects withcardiovascular disorders. “Cardiovascular disorder” refers to astructural and functional abnormality of the heart and blood vessels,comprised of diseases including but not limited to, atherosclerosis,coronary artery disease, arrhythmia, heart failure, hypertension,diseases of the aorta and its branches, disorders of the peripheralvascular system, aneurysm, endocarditis, pericarditis, heart valvedisease. It may be congenital or acquired. One of the main pathologicalfeature of all these diseases is clogged and hardened arteries,obstructing the blood flow to the heart. The effects differ dependingupon which vessels are clogged with plaque. The arteries carrying oxygenrich blood, if clogged, result in coronary artery disease, chest pain orheart attack. If the arteries reaching the brain are affected, it leadsto transient ischemic attack or stroke. If the vessels in arms or legsare affected, leads to peripheral vascular disease. Because a number ofcardiovascular diseases may also be related to or arise as a consequenceof thrombocytopathies, there is some overlap between disorders that areconsidered under heading cardiovascular disorders andthrmobocytopathies. For the purpose of this invention, in the case ofsuch an overlapping disorder, it may be considered either acardiovascular disorder or a thrombocytopathy.

STIM1 is located on the endoplasmic reticulum (ER) and functions as acalcium sensor. Orai1 is a pore forming subunit of calcium channellocated on the plasma membrane, the depletion of calcium in theendoplasmic reticulum is sensed by STIM1, and calcium enters via Orai1to refill the endoplasmic reticulum. This pathway of filling the calciumis called store operated calcium entry (SOCE), which plays an importantrole in calcium homeostasis, cellular dysfunction and has a significantimportance in cardiovascular diseases. In cardiomyocytes, calcium is notonly involved in excitation-contraction coupling but also acts as asignalling molecule promoting cardiac hypertrophy. Hypertrophic heartsare susceptible to abnormalities of cardiac rhythm and have impairedrelaxation. Vascular smooth muscle cells (VSMCs) are responsible for themaintenance of vascular tone. VSMCs disorders, usually manifested as aphenotype change, are involved in the pathogenesis of major vasculardiseases such as atherosclerosis, hypertension and restenosis. SOCE wasalso found increased in metabolic syndrome (MetS) swine coronary smoothmuscle cells. The compound of this invention can be used to treatneointimal hyperplasia, occlusive vascular diseases, MetS—which is acombination of medical disorders including coronary artery disease,stroke and type 2 diabetes, abdominal aortic aneurysm, angina, transientischemic attack, stroke, peripheral artery occlusive disease whichincludes inflammation, complement activation, fibrinolysis, angiogenesisand/or diseases related to FXII-induced kinin formation such ashereditary angioedema, bacterial infection of the lung, trypanosomeinfection, hypotensive shock, pancreatitis, chagas disease,thrombocytopenia or articular gout, myocardial infarction, portal veinthrombosis which leads to hypertension, pulmonary hypertension, deepvein thrombosis, jugular vein thrombosis, systemic sepsis, pulmonaryembolism, and papilledema, Budd-Chiari syndrome, Paget-Schroetterdisease, cerebral venous sinus thrombosis ischemic cardiomyopathy,hypertrophic cardiomyopathy, arrhythmogenic right ventricularcardiomyopathy, Prinzmetal angina, angina pectoris, chronic venousinsufficiency, acute coronary syndrome, endocarditis, conceptualapraxia, pulmonary valve stenosis, thrombophlebitis, ventriculartachycardia, temporal arteritis, tachycardia, paroxysmal atrialfibrillation, persistent atrial fibrillation, permanent atrialfibrillation, respiratory sinus arrhythmia, carotid artery dissection,cerebrovascular diseases include, hemorrhagic stroke and ischemic stroke(where the thrombo-inflammatory cascade results in infarct growth),cardiomegaly, endocarditis, pericarditis, pericardial effusion. Valvularheart disease, vascular diseases or vascular inflammation is the resultof ruptured atherosclerotic plaque which initiates thrombus formation.Platelet activation play an important role in vascular inflammationleading to myocardial infarction and ischaemic stroke, the compound ofthis invention will prevent platelet activation and plaque formation andwould also be useful to treat all peripheral vascular diseases (PVD),pulmonary thromboembolism, and venous thrombosis.

“Treatment of cardiovascular disorders” herein refers to administering acompound or a composition of the invention alone or in combination withother agents to a subject, who has a cardiovascular disease, a sign orsymptom of such a disease or a risk factor towards such a disease, witha purpose to cure, relieve, alter, affect, or prevent such disorder orsign or symptom of such a disease, or the predisposition towards it.

In yet another embodiment, the invention is directed to the treatment of“thrombocytopathies” by administering an effective amount of a compoundof the present invention.

Thrombocytopathies: The compounds of this invention can be used to treatsubjects with thrombocytopathies. Thrombocytopathy is an abnormality ofplatelets or its functions. It may be congenital or acquired. It maycause a thrombotic or a bleeding tendency or may be part of a widerdisorder such as myelodysplasia. Thrombocytopathies include suchvascular disorders that arise due to dysfunction of platelets orcoagulation system or diseases or complications that arise as a resultof partial or complete restriction of blood flow to different organs orsystems due to such thrombocytopathies. Thrombocytopathies will thusinclude without limitation; diseases due to superficial vein thrombosis,diseases due to deep vein thrombosis, diseases due to arterialthrombosis, peripheral vascular diseases, thrombophilia,thrombophlebitis, embolisms, thromboembolism, ischemic cardiovasculardiseases including but not limited to myocardial ischemia, angina,ischemic cerebrovascular diseases including but not limited to stroke,transient ischemia attack, cerebral venous sinus thrombosis (CVST) andcomplications arising due to thrmobocytopathies. Besides this, thedisorder related to venous or arterial thrombus formation can beinflammation, complement activation, fibrinolysis, angiogenesis and/ordiseases related to FXII-induced kinin formation such as hereditaryangioedema, bacterial infection of the lung, trypanosome infection,hypotensitive shock, pancreatitis, chagas disease, thrombocytopenia orarticular gout.

Under normal circumstances, when the endothelial cells lining bloodvessels are breached, platelets interact with von Willebrand factor(vWF) via the membrane glycoprotein 1b complex to help seal the breach.Glycoprotein IIb/Ia complex attracts other platelets, which combine toform aggregates. The platelets contain granules which break down torelease fibrinogen, vWF, platelet-derived growth factor adenosine5′-diphosphate (ADP), calcium and 5-hydroxytryptamine (5-HT)-serotonin.All this helps to promote the formation of a haemostatic plug (primaryhaemostasis). Activated platelets also synthesise thromboxane A2 fromarachidonic acid as well as presenting negatively charged phospholipidson the outer leaflet of the platelet membrane bilayer. This negativesurface provides binding sites for enzymes and cofactors of thecoagulation system. The total effect is therefore to stimulate thecoagulation system to form a clot (secondary haemostasis).

Thus physiological platelet activation and thrombus formation areessential to stop bleeding in case of vascular injury, whereas underpathological conditions this may lead to vessel occlusion due toinadequate triggering of the same process in diseased vessels leading tothrombosis, thromboembolism or tissue ischemia of vital organs. Acentral step in platelet activation is agonist-induced elevation of theintracellular Ca(2+) concentration. This happens on the one hand throughthe release of Ca(2+) from intracellular stores and on the other handthrough Ca(2+) influx from the extracellular space. In platelets, themajor Ca(2+) influx pathway is through store operated Ca(2+) entry(SOCE), induced by store depletion. STIM1 is the the Ca(2+) sensor inthe endoplasmic reticulum (ER) membrane, whereas Orai1 is the majorstore operated Ca(2+) (SOC) channel in the plasma membrane, which play akey role in platelet SOCE.

“Treatment of thrombocytopathy” herein refers to administering acompound or a composition of the invention alone or in combination withother agents to a subject, who has a thrombocytopathy, a sign or symptomor complication of such a disease or a risk factor towards such adisease, with the purpose to cure, relieve, alter, affect, or preventsuch a disorder or sign or symptom, or the predisposition towards it.

General Methods of Preparation

The compounds of the present invention, including compounds of generalFormula (I) and specific examples are prepared through the reactionsequences illustrated in synthetic Schemes 1 to 4 wherein A, B, L, R₁,R₂, R₃, ring E and ‘n’ are as defined herein above. Starting materialsare commercially available or may be prepared by the proceduresdescribed herein or by the procedures known in the art. Furthermore, inthe following synthetic schemes, where specific acids, bases, reagents,coupling agents, solvents, etc., are mentioned, it is understood thatother bases, acids, reagents, coupling agents, solvents etc., known inthe art may also be used and are therefore included within the scope ofthe present invention. Variations in reaction conditions and parameterslike temperature, pressure, duration of reaction, etc., which may beused as known in the art are also within the scope of the presentinvention. All the isomers of the compounds described in these schemes,unless otherwise specified, are also encompassed within the scope ofthis invention.

The compounds obtained by using the general reaction sequences may be ofinsufficient purity. These compounds can be purified by using any of themethods for purification of organic compounds known in the art, forexample, crystallization or silica gel or alumina column chromatographyusing different solvents in suitable ratios. Unless mentioned otherwise,room temperature (RT) refers to a temperature in the range of 22 to 27°C.

¹H-NMR spectra of the compounds of the present invention were recordedusing a BRUCKNER instrument (model: Avance-III), 400 MHz. Liquidchromatography-mass spectra (LCMS) of the compounds of the presentinvention were recorded using Agilent ion trap model 6320 and ThermoScientific Single Quad model MSQ plus instruments. IUPAC nomenclaturefor the compounds of the present invention was used according toChemBioDraw Ultra 12.0 software.

As depicted in synthetic Scheme-1, the synthesis of compounds of theFormula (5), that served as precursor(s) of the compounds of theinvention (Ia) wherein A, B, R₁, R₂, R₃, ring E and ‘n’ are as definedherein above, began with cyclocondensation of hydrazine derivative(s) ofthe Formula (1) with appropriately substituted 2,4-diones of the Formula(2) to provide the pyrazole compounds of the Formula (3). Condensationsof this type typically afford compounds of the Formula (3) in aregioselective manner as known in the art by using an acid catalyst suchas p-toluenesulfonic acid, hydrochloric acid, sulfuric acid etc., and insuitable solvent. Compounds of the Formula (3) undergoes oxidationreaction with suitable oxidants such as potassium permanganate, ozone,sodium metaperiodate, ruthenium chloride and the like; affordedcompounds of the Formula (4). This compound of the Formula (4) isfurther transformed to compounds of the Formula (5) by following theprocedure known in the art.

Compounds of the Formula (Ia) prepared by coupling of halogenderivatives of the Formula (5) with amide/amine derivatives of theFormula (6) in presence of suitable reagent and solvent.

Alternatively, nitro derivatives of the Formula (5) where X′ is nitrogroup; are transformed to amine derivatives of the Formula (7) withhydrogen gas in the presence of metal catalysts known in the art such aspalladium on carbon, palladium hydroxide and the like; Finally, compoundof the Formula (7) is coupled with compound of Formula (8) by reductiveamination as per the methods known in the art to obtain amino compoundof Formula (Ia) where L is NR₁₁CR_(a)R_(b). Compound of Formula (7) canalso converted to compound of Formula (Ia) where L is an amide linker,by following suitable amide coupling reaction with compound of Formula(8).

Alternatively, carboxylate derivatives of the Formula (5) is coupledwith amino compound of Formula (5a) to give compounds of the Formula(Ib) where L is C(O)NR₁₁.

As described in synthetic Scheme-2, cyclocondensation of hydrazinecompound of the Formula (1) with appropriately substituted enol ether(s)of the Formula (9) to provide the pyrazole compound of the Formula (10)regioselectively (Synthesis, 2005, 16, 2744). The pyrazole compound ofthe Formula (10) is converted to acid compound which further convertedto compound of Formula (12) by following the methods as described in thesynthetic Scheme-1. Finally compound of the Formula (IIa) where L is—NR₁₁C(O)— or —NR₁₁CR_(a)R_(b)— or Formula (IIb) where L is C(O)NR₁₁,obtained from compound of formula (11) by following the suitablereaction step(s) as described in the synthetic Scheme-1.

In another approach as described in the synthetic Scheme 3, the halogencompound of Formula (10) undergoes carboxylation to give acid or estercompound of the Formula (14). Alternatively, compound of the Formula(10) is reacted with metal cyanides such as zinc cyanide, coppercyanide, sodium cyanide, potassium ferrocyanide or mixture(s) thereof;in presence of metal catalysts like Pd₂(dba)₃, Pd(PPh₃)₄; in presence ofligands such as bis(diphenylphosphino)ferrocene, dibenzylideneacetone,xantphos or mixture(s) thereof. The said transformation may also becarried out by other methods known in the art. Compounds of the Formula(15) are converted to the compounds of the Formula (16) and in turn tothe compounds of the invention of the Formula (I %) wherein A, B, R₁,R₂, R₃, ring E and ‘n’ are as defined herein above, by following themethods known in the art or as described in synthetic Scheme 1.

Alternatively, as depicted in synthetic Scheme 4, compound of theFormula (15) is converted to compound of the Formula (17) by followingthe methods known in the art. Compound of the Formula (17) istransformed to compound of the invention of the Formula (IIb) wherein A,B, R₁, R₂, R₃, ring E and ‘n’ are as defined herein above, by reactingwith compounds of the Formula (14) by amidation by following the methodsdescribed in the synthetic Scheme 1 or as known in the art.

Experimental

The invention is further illustrated by the following examples which areprovided merely to be exemplary of the invention and do not limit thescope of the invention. The examples set forth below demonstrate thesynthetic procedures for the preparation of the representativecompounds. Certain modifications and equivalents will be apparent tothose skilled in the art and are intended to be included within thescope of the invention. The aforementioned patents and patentapplications are incorporated herein by reference.

Unless otherwise stated, work-up implies the following operations:distribution of the reaction mixture between the organic and aqueousphase, separation of layers, drying the organic layer over sodiumsulfate, filtration and evaporation of the organic solvent.Purification, unless otherwise mentioned, implies purification by silicagel chromatographic techniques, generally using ethyl acetate/petroleumether mixture of a suitable polarity as the mobile phase.

Intermediates Intermediate-15-(1-(5-Bromopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one

Step-1:5-Bromo-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine:A mixture of 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione (7.0 g, 34.0mmol) and 5-bromo-2-hydrazinylpyridine hydrochloride (7.62 g, 34.0 mmol)in acetic acid (20 mL) was stirred at 70° C. for 1.5 h. The reactionmixture was cooled to room temperature (RT) and then diluted with ethylacetate (200 mL) and basified with aqueous sodium hydroxide solution(10%, pH 7-8). The resulting slurry was filtered and the filtrate waswashed with water (50 mL), dried (Na₂SO₄) and filtered. The filtrate wasrotary evaporated and the crude product was purified by flash columnchromatography (silica gel, 20% ethyl acetate-hexanes as eluent) toafford 10 g (82%) of the title compound as white semisolid. ¹HNMR (400MHz, CDCl₃) δ 8.54 (brs, 1H), 8.02 (dd, J=2.5 & 8.5 Hz, 1H), 7.64 (d,J=8.5 Hz, 1H), 7.45 (d, J=1.5 Hz, 1H), 6.93 (s, 1H), 6.62 (d, J=3.5 Hz,1H), 6.47 (dd, J=3.5 & 1.5 Hz, 1H); ESI-MS (m/z) 358, 360 [(MH)⁺,Br^(79,81)].

Step-2:1-(5-Bromopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid: To a stirred solution of step-1 intermediate (10 g, 27.9 mmol) inacetone: water (1:1, 200 mL) at 0° C. was drop-wise added a solution ofKMnO4 (30.9 g, 195 mmol) in water (50 mL). The resulting mixture wasstirred at room temperature for 15 min and then at 60° C. for 4 h. Thereaction was cooled back down to room temperature and 2-propanol (40 mL)was added to the above mixture and stirring was continued for another 4h at room temperature. The reaction was filtered through celite and thefiltrate was evaporated under reduced pressure to dryness. The residuewas dissolved in 1N aqueous sodium hydroxide solution (300 mL) andwashed with ethyl acetate-hexanes (10%). The aqueous layer was acidifiedwith aqueous hydrochloric acid (10%, pH 4.0) and then extracted withethyl acetate (3×100 mL). The combined organic layers were washed withbrine (100 mL), dried (Na₂SO₄) and filtered. The filtrate wasconcentrated under vacuum to afford 6.0 g (64%) of the title compound asa white semi solid. ESI-MS (m/z) 336, 338 [(MH)⁺, Br^(79,81)].

Step-3: Ethyl1-(5-bromopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate:To a stirred solution of step-2 intermediate (6.90 g, 20.53 mmol) inethanol (100 mL) at room temperature was added sulfuric acid (6 mL)drop-wise and the reaction was stirred at 100° C. for 18 h. The reactionwas cooled to room temperature and the solvent was evaporated undervacuum. Water (100 mL) was added to the above obtained residue, basifiedwith aqueous sodium carbonate solution (10%, 30 mL) and extracted withethyl acetate (3×100 mL). The combined organic layers were washed withwater (100 mL), brine (100 mL), dried (Na₂SO₄) and filtered. Thefiltrate was concentrated under vacuum to afford 6.0 g (80%) of thetitle compound as a white semi-solid. ¹HNMR (400 MHz, DMSO-d₆) δ 8.72(d, J=2.5 Hz, 1H), 8.38 (dd, J=2.5 & 8.5 Hz, 1H), 7.83 (d, J=8.5 Hz,1H), 7.62 (s, 1H), 4.25 (q, J=7.0 Hz, 2H), 1.16 (t, J=7.0 Hz, 3H);ESI-MS (m/z) 364, 366 [(MH)⁺, Br^(79,81)].

Step-4:1-(5-Bromopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carbohydrazide:A mixture of step-3 intermediate (6.0 g, 16.48 mmol) and hydrazinehydrate (2.59 mL, 82 mmol) in ethanol (100 mL) was stirred at 100° C.overnight. Reaction mixture was cooled down to room temperature and thesolvent was evaporated under vacuum. The residue was triturated withtoluene to obtain 4.0 g (70%) of title compound as a white solid. ¹HNMR(400 MHz, DMSO-d₆) δ 9.99 (s, 1H, D₂O exchangeable), 8.64 (d, J=2.5 Hz,1H), 8.30 (dd, J=2.5 & 8.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.30 (s,1H), 4.55 (brs, 2H, D₂O exchangeable); ESI-MS (m/z) 350, 352 [(MH)⁺,Br^(79,81)].

Step-5:5-(1-(5-Bromopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1,3,4-oxadiazol-2(3H)-one:To a stirred and (0° C.) cooled solution of step-4 intermediate (4.0 g,11.43 mmol) and DIPEA (3.99 mL, 22.85 mmol) in DCM (50 mL) was added asolution of triphosgene (1.35 g, 4.57 mmol) in DCM (20 mL) over a periodof 10 min. Reaction mixture was warmed to room temperature and stirredovernight. The reaction was cooled to 0° C. and quenched with ice water(5 mL). Water (25 mL) was added to the above mixture followed by DCM(100 mL). The layers were separated and the aqueous layer was extractedwith DCM (2×100 mL). The combined organic layers were washed with brine(50 mL), dried (Na₂SO₄) and filtered. The filtrate was rotary evaporatedto afford 3.0 g (70%) of the title compound as pink semisolid. ¹HNMR(400 MHz, DMSO-d₆) δ 12.95 (s, 1H, D₂O exchangeable), 8.71 (d, J=2.5 Hz,1H), 8.39 (dd, J=2.5 & 8.5 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.70 (s,1H); ESI-MS (m/z) 376, 378 [(MH)⁺, Br^(79,81)].

Step-6:5-(1-(5-Bromopyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one:To a (0° C.) cooled and stirred solution of step-5 intermediate (3.0 g,7.98 mmol) in DMF (25 mL) was added potassium carbonate (1.0 g, 7.18mmol) and methyl iodide (0.50 mL, 7.98 mmol) and the reaction wasstirred at room temperature for 18 h. Ice cooled water (10 mL) was thenadded to the above reaction mixture and the separated solid was filteredand dried to afford 2.50 g (80%) of the desired product as a whitesolid. ¹HNMR (400 MHz, CDCl₃) δ 8.47 (d, J=2.0 Hz, 1H), 8.05 (dd, J=2.0& 8.5 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.12 (s, 1H), 3.51 (s, 3H);ESI-MS (m/z) 390, 392 [(MH)⁺, Br^(79,81)].

Intermediate-25-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one

Step-1:1-(5-Bromopyridin-2-yl)-3-(furan-2-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-ol:To a stirred solution of1,1,1-trifluoro-4-(furan-2-yl)-4-methoxybut-3-en-2-one (129 g, 585 mmol;prepared by following the procedure described in Tett Lett., 2002, 43,8701) in chloroform (600 mL) was added solid5-bromo-2-hydrazinylpyridine (prepared by the reaction of2,5-dibromopyridine with hydrazine hydrate, 110.0 g, 585 mmol) in 10portions at 0° C. over a period of 30 min. The reaction was stirred for1 h at room temperature, and then at 50° C. for 36 h. The reaction wascooled to 0° C. before the addition of water (200 mL) and chloroform(500 mL). The layers were separated and the aqueous layer was extractedwith chloroform (3×200 mL). The combined organic layers were washed withbrine (200 mL), dried (Na₂SO₄) and filtered. The filtrate was rotaryevaporated and the crude product was purified by flash columnchromatography (5% ethyl acetate-hexanes system as eluent) to afford 90g (40%) of the title compound as a white solid. ¹HNMR (400 MHz, CDCl₃) δ8.17 (d, J=2.5 Hz, 1H), 7.96 (s, 1H, D₂O Exchangeable), 7.75 (dd, J=2.5& 8.5 Hz, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 6.76 (d,J=2.5 Hz, 1H), 6.54 (dd, J=1.5 & 2.5 Hz, 1H), 3.71 (d, J=18.5 Hz, 1H),3.56 (d, J=18.5 Hz, 1H); ESI-MS (m/z) 376, 378 [(MH)⁺, Br^(79,81)].

Step-2: 5-Bromo-2-(3-(furan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine: To a (5° C.) cooled solution of step-1 intermediate (80 g, 213mmol) in benzene (600 mL) was added SOCl₂ (38.8 mL, 532 mmol). Afterstirring for 15 min at 5° C., pyridine (51.6 mL, 638 mmol) was added atthe same temperature and the reaction was continued to stir for another15 min. Ice cooled water (100 mL) was then added to the above reactionmixture followed by ethyl acetate (300 mL). The layers were separatedand the aqueous layer was extracted with ethyl acetate (2×200 mL). Thecombined organic layers were washed with saturated aqueous NaHCO₃ (300mL), brine (200 mL), dried (Na₂SO₄) and filtered. The filtrate wasconcentrated under vacuum to afford 70 g (92%) of the title compound aswhite solid. ¹HNMR (400 MHz, CDCl₃) δ 8.55 (d, J=1.5 Hz, 1H), 7.97 (dd,J=2.0 & 8.5 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.53 (d, J=1.5 Hz, 1H),7.11 (s, 1H), 6.84 (d, J=3.0 Hz, 1H), 6.53 (dd, J=3.0 & 1.5 Hz, 1H);ESI-MS (m/z) 358, 360 [(MH)⁺, Br^(79,81)].

Step-3:Ethyl-1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate:The title compound was prepared by following the similar proceduredescribed for step-3 of Intermediate-1 using above step-2 intermediate.¹HNMR (400 MHz, CDCl₃) δ 8.59 (d, J=2.5 Hz, 1H), 8.03 (dd, J=2.5 & 8.5Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.37 (s, 1H), 4.46 (q, J=7.0 Hz, 2H),1.43 (t, J=7.0 Hz, 3H); ESI-MS (m/z) 364, 366 [(MH)⁺, Br^(79,81)].

Step-4:5-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one:The title compound was prepared by following the similar proceduresequentially as described in Step-4, Step-5, and Step-6 ofIntermediate-1 using above step-3 intermediate. ¹HNMR (400 MHz, DMSO-d₆)δ 8.75 (d, J=2.5 Hz, 1H), 8.38 (dd, J=2.5 & 8.5 Hz, 1H), 7.88 (d, J=8.5Hz, 1H), 7.75 (s, 1H), 3.43 (s, 3H); ESI-MS (m/z) 390, 392 [(MH)⁺,Br^(79,81)].

Intermediate-36-(3-(4-Methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinicacid

Step-1:6-(3-(4-Methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinonitrile:In a sealed tube containing a suspension of Intermediate-2 (1.0 g, 2.56mmol), dicyanozinc (0.90 g, 7.69 mmol) in dioxane (8 mL) was purgednitrogen gas for 30 min and, tetrakis(triphenylphosphine)palladium(0)(296 mg, 0.256 mmol) was added. The resulting mixture was thoroughlydeoxygenated by purging nitrogen gas and the sealed tube was capped andstirred at 110° C. for 5 h. The reaction mixture was cooled back down toroom temperature and ammonium hydroxide solution (1.0 mL) was addedfollowed by water (10 mL) and then diluted with ethyl acetate (50 mL).The layers were separated and the aqueous layer was extracted with ethylacetate (2×30 mL). The combined organic layers were washed withsaturated aqueous NaHCO₃ (50 mL), dried (Na₂SO₄) and filtered. Thefiltrate was rotary evaporated and the crude product was purified byflash column chromatography (20% ethyl acetate-hexanes as eluent) toafford 850 mg (99%) of the title compound as white solid. ¹HNMR (400MHz, DMSO-d₆) δ 9.10 (d, J=2.5 Hz, 1H), 8.62 (dd, J=2.5 & 8.5 Hz, 1H),8.13 (d, J=8.5 Hz, 1H), 7.83 (s, 1H), 3.44 (s, 3H); ESI-MS (m/z) 337(MH)⁺.

Step-2:5-6-(3-(4-Methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinicacid: In a sealed tube containing a solution of6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinonitrile(0.80 g, 2.37 mmol) in methanesulfonic acid (5 mL, 77 mmol) and water (4mL) was heated at 70° C. for 6 h. The reaction mixture was then cooledto room temperature and water (10 mL) was added to the above mixturefollowed by ethyl acetate (50 mL). The layers were separated and theaqueous layer was extracted with ethyl acetate (2×30 mL). The combinedorganic layers were washed with saturated aqueous NaHCO₃ (30 mL), dried(Na₂SO₄) and filtered. The filtrate was rotary evaporated to afford 500mg (60%) of the title compound as white solid. ¹HNMR (400 MHz, DMSO-d₆)δ 13.71 (s, 1H, D₂O exchangeable), 9.01 (d, J=2.5 Hz, 1H), 8.55 (dd,J=2.5 & 8.5 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.80 (s, 1H), 3.40 (s, 3H);ESI-MS (m/z) 356 (MH)⁺.

Intermediate-43-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5,5-dimethylisoxazol-4(5H)-one

Step-1:1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylicacid: The title compound was prepared from Step-2 of Intermediate-2using potassium permanganate by following the similar procedure asdescribed in Step-2 of Intermediate-1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.73(d, J=2.5 Hz, 1H), 8.36 (dd, J=2.5 & 8.5 Hz, 1H), 7.88 (d, J=8.5 Hz,1H), 7.51 (s, 1H); ESI-MS (m/z) 336, 338 [(M)⁺, Br^(79,81)].

Step-2:3-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5,5-dimethylisoxazol-4(5H)-one: The title compound was prepared from1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylicacid by following the analogues procedure as described in WO2012056748.¹HNMR (400 MHz, CDCl₃) δ 8.60 (d, J=2.5 Hz, 1H), 8.02 (dd, J=2.5 & 8.5Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.52 (s, 1H), 1.53 (s, 6H); ESI-MS(m/z) 403, 405 [(MH)⁺, Br^(79,81)].

Intermediate-51′-(5-Bromopyridin-2-yl)-1,4,4-trimethyl-5′-(trifluoromethyl)-1H,1′H-[3,3′-bipyrazol]-5(4H)-one

Step-1: Ethyl3-(1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,2-dimethyl-3-oxopropanoate:To (0° C.) cooled and stirred solution of1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylicacid (6.0 g, 17.85 mmol) in DCM (30 mL) was added oxalyl chloride (4.69mL, 53.6 mmol) followed by catalytic amount of DMF (0.14 mL, 1.78 mmol).The resulting mixture was warmed to room temperature and then stirredfor 1 h. Reaction mass was concentrated under vacuum and the crudeproduct was dried under vacuum.

To a freshly prepared solution of lithium diisopropyl amide (prepared bythe addition of n-butyl lithium (12.27 mL, 19.63 mmol) to a solution ofdiisopropylamine (2.80 mL, 19.63 mmol) in THF (20 mL)) at −78° C., wasdrop-wise added a solution of ethyl isobutyrate (2.21 mL, 16.36 mmol) inTHF (10 mL). The resulting mixture was stirred at the same temperaturefor 1 h and then the above prepared solution of1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbonylchloride (5.80 g, 16.36 mmol) in THF (20 mL) was drop-wise added. Theresulting mixture was stirred at −78° C. for 30 min, then graduallywarmed to room temperature over 1 h and then stirred for another 1 h atroom temperature. The reaction was cooled to 0° C. and then quenchedwith saturated ammonium chloride solution (20 mL) and then diluted withethyl acetate (100 mL). The layers were separated and the aqueous layerwas extracted with ethyl acetate (2×50 mL). The combined organic layerswere washed with brine (50 mL), dried (Na₂SO₄) and filtered. Thefiltrate was rotary evaporated and the crude product was purified byflash column chromatography (10% ethyl acetate in hexanes as eluent) toafford 2.50 g (35%) of the title compound as a white solid. ¹HNMR (400MHz, CDCl₃) δ 8.58 (d, J=2.0 Hz, 1H), 8.02 (dd, J=2.0 & 8.0 Hz, 1H),7.73 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 4.11 (q, J=7.0 Hz, 2H), 1.60 (s,3H), 1.58 (s, 3H), 1.04 (t, J=7.0 Hz, 3H); ESI-MS (m/z) 434, 436 [(MH)⁺Br^(79,81)].

Step-2:3-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,2-dimethyl-3-oxopropanehydrazide:A mixture of step-1 intermediate (2.40 g, 5.53 mmol) and hydrazinehydrate (0.87 mL, 27.6 mmol) in ethanol (30 mL) was heated at 80° C.overnight. The reaction mixture was cooled to room temperature and thesolvent was then evaporated under vacuum. The residue was trituratedwith toluene to obtain 2.0 g (86%) of title compound as a white solid.¹HNMR (400 MHz, DMSO-d₆) δ 11.78 (s, 1H, D₂O exchangeable), 8.72 (d,J=2.0 Hz, 1H), 8.38 (dd, J=2.0 & 8.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H),7.54 (s, 1H), 1.42 (s, 6H); ESI-MS (m/z) 420, 422 [(MH)⁺, Br^(79,81)].

Step-3:1′-(5-Bromopyridin-2-yl)-4,4-dimethyl-5′-(trifluoromethyl)-1H,1′H-[3,3′-bipyrazol]-5(4H)-one:To a stirred and (0° C.) cooled solution of step-2 intermediate (2.0 g,4.76 mmol) and DIPEA (1.66 mL, 9.52 mmol) in DCM (20 mL) was added asolution of triphosgene (560 mg, 1.90 mmol) in DCM (5 mL) over a periodof 10 min. The reaction mixture was warmed to room temperature and thenstirred overnight. Reaction was cooled down to 0° C. and then quenchedwith ice water (5 mL). Water (25 mL) was added to the reaction followedby DCM (50 mL). The layers were separated and the aqueous layer wasextracted with DCM (2×50 mL). The combined organic layers were washedwith brine (50 mL), dried (Na₂SO₄) and filtered. The filtrate was rotaryevaporated to afford 1.50 g (78%) of the title compound as semisolid.¹HNMR (400 MHz, CDCl₃) δ 8.85 (s, 1H, D₂O exchangeable), 8.59 (d, J=2.0Hz, 1H), 8.02 (dd, J=2.0 & 8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.31 (s,1H), 1.60 (s, 6H); ESI-MS (m/z) 402, 404 [(MH)⁺, Br^(79,81)].

Step-4:1′-(5-Bromopyridin-2-yl)-1,4,4-trimethyl-5′-(trifluoromethyl)-1H,1′H-[3,3′-bipyrazol]-5(4H)-one:To a (0° C.) cooled and stirred solution of step-3 intermediate (1.50 g,3.73 mmol) in DMF (10 mL) was added potassium carbonate (619 mg, 4.48mmol) and methyl iodide (0.28 mL, 4.48 mmol) and the reaction wasstirred at room temperature for 18 h. Ice cooled water (10 mL) was addedto the above reaction mixture and the separated solid was filtered anddried to afford 1.50 g (97%) of the desired product as a white solid.¹HNMR (400 MHz, CDCl₃) δ 8.59 (d, J=2.0 Hz, 1H), 8.03 (dd, J=2.0 & 8.0Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.32 (s, 1H), 3.44 (s, 3H), 1.55 (s,6H); ESI-MS (m/z) 416, 418 [(MH)⁺, Br^(79,81)].

Intermediate-63-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-1,2,4-oxadiazol-5(4H)-one

Step-1:1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide:To a (0° C.) cooled solution of1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylicacid (5.0 g, 14.88 mmol) in DCM (50 mL) was added oxalyl chloride (3.91mL, 44.6 mmol) followed by catalytic amount of DMF (0.14 mL, 1.78 mmol).The resulting mixture was stirred at room temperature for 1 h. Theexcess of oxalyl chloride was removed under vacuum and the residue wasagain diluted with DCM (100 mL). Aqueous ammonium hydroxide solution(29.0 mL, 744 mmol) was added drop-wise to the above mixture at 0° C.and the reaction mixture was stirred at room temperature overnight. Thesolvent was evaporated under vacuum and concentrate was diluted withethyl acetate (100 mL). The layers were separated and the aqueous layerwas extracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with brine (100 mL), dried (Na₂SO₄) and filtered. Thefiltrate was rotary evaporated to afford 4.0 g (80%) of the titlecompound as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.73 (d, J=2.0 Hz,1H), 8.41 (dd, J=2.0 & 8.0 Hz, 1H), 8.09 (s, 1H, D₂O exchangeable), 7.97(d, J=8.0 Hz, 1H), 7.70 (s, 1H, D₂O exchangeable), 7.52 (s, 1H); ESI-MS(m/z) 335, 337 [(MH)⁺, Br^(79,81)].

Step-2:1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbonitrile:To a stirred and (0° C.) cooled solution of step-1 intermediate (4.0 g,11.94 mmol) in POCl₃ (22.25 mL, 239 mmol) was added pyridine (1.93 mL,23.87 mmol). The resulting mixture was warmed to room temperature andthen stirred at 80° C. for 3 h. The reaction was cooled to roomtemperature and the excess of POCl₃ was evaporated under vacuum. Water(50 mL) was added to the above obtained residue, basified with aqueoussaturated sodium bicarbonate solution (50 mL) and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with water(50 mL), brine (50 mL), dried (Na₂SO₄) and filtered. The filtrate wasconcentrated under vacuum to afford 3.20 g (85%) of the title compoundas a white solid. ¹HNMR (400 MHz, CDCl₃) δ 8.61 (d, J=2.0 Hz, 1H), 8.08(dd, J=2.0 & 8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.26 (s, 1H); ESI-MS(m/z) 317, 319 [(MH)⁺, Br^(79,81)].

Step-3:1-(5-Bromopyridin-2-yl)-N-hydroxy-5-(trifluoromethyl)-1H-pyrazole-3-carboximidamide:A mixture of step-2 intermediate (150 mg, 0.473 mmol), hydroxylaminehydrochloride (82 mg, 1.183 mmol) and Na₂CO₃ (125 mg, 1.183 mmol) inethanol (10 mL) was stirred at 85° C. for 6 h. Reaction mixture wascooled to room temperature and the solvent was evaporated under vacuum.Water (10 mL) was added to the obtained residue and extracted with ethylacetate (2×25 mL). The combined organic layers were washed with water(20 mL), brine (20 mL), dried (Na₂SO₄) and filtered. The filtrate wasconcentrated under vacuum to afford 106 mg (64%) of the title compoundas a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 9.96 (s, 1H), 8.69 (d,J=2.0 Hz, 1H), 8.37 (dd, J=2.0 & 8.0 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H),7.23 (s, 1H), 5.93 (s, 2H); ESI-MS (m/z) 350, 352 [(MH)⁺, Br^(79,81)].

Step-4:3-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,2,4-oxadiazol-5(4H)-one:To a stirred and (0° C.) cooled solution of step-3 intermediate (106 mg,0.303 mmol) and DIPEA (0.106 mL, 0.606 mmol) in DCM (15 mL) was addeddrop-wise a solution of triphosgene (35 mg, 0.121 mmol) in DCM (3 mL).The reaction was stirred at room temperature for 1 h before quenchingwith ice water (5 mL). Water (10 mL) was added to the above mixturefollowed by DCM (25 mL). The layers were separated and the aqueous layerwas extracted with DCM (2×15 mL). The combined organic layers werewashed with brine (15 mL), dried (Na₂SO₄) and filtered. The filtrate wasrotary evaporated to afford 100 mg (88%) of the title compound as brownsolid. ESI-MS (m/z) 376, 378 [(MH)⁺, Br^(79,81)].

Step-5:3-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-1,2,4-oxadiazol-5(4H)-one:To a (0° C.) cooled and stirred solution of step-4 intermediate (100 mg,0.266 mmol) in DMF (3 mL) was added potassium carbonate (73 mg, 0.532mmol) and methyl iodide (33 μL, 0.532 mmol) and the reaction was stirredat room temperature for 18 h. Ice cooled water (3 mL) was added to thereaction and extracted with ethyl acetate (2×15 mL). The combinedorganic layers were washed with water (3×10 mL), brine (10 mL), dried(Na₂SO₄) and filtered. The filtrate was rotary evaporated and the crudeproduct was purified by flash column chromatography to afford 25 mg(24%) of the title compound as white solid. ¹HNMR (400 MHz, CDCl₃) δ8.64 (d, J=2.0 Hz, 1H), 8.07 (dd, J=2.0 & 8.0 Hz, 1H), 7.73 (d, J=8.0Hz, 1H), 7.44 (s, 1H), 3.68 (s, 3H); ESI-MS (m/z) 390, 392 [(MH)⁺,Br^(79,81)].

Intermediate-71-(5-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,2-dimethyl-1,3,4-oxadiazol-3(2H)-yl)ethanone

Step-1:1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbohydrazide:A mixture of ethyl1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate(33 g, 91 mmol) and hydrazine hydrate (17.07 mL, 544 mmol) in ethanol(330 mL) was heated at 100° C. overnight. The reaction mixture wascooled back down to room temperature and the solvent was evaporatedunder vacuum. The residue was triturated with toluene to obtain 30 g(95%) of the title compound as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ9.97 (s, 1H, D₂O exchangeable), 8.72 (d, J=2.5 Hz, 1H), 8.40 (dd, J=2.5& 8.5 Hz, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.54 (s, 1H), 4.58 (s, 2H, D₂Oexchangeable); ESI-MS (m/z) 350, 352 [(MH)⁺, Br^(79,81)].

Step-2:1-(5-Bromopyridin-2-yl)-N′-(propan-2-ylidene)-5-(trifluoromethyl)-1H-pyrazole-3-carbohydrazide:A solution of step-1 intermediate (1.0 g, 2.86 mmol) in acetone: hexane(1:1, 12 mL) was stirred at 70° C. for 3 h. The reaction was then cooledto room temperature and the solvent was evaporated under vacuum toafford 800 mg (72%) of the title compound as white solid. ESI-MS (m/z)390, 392 [(MH)⁺, Br^(79,81)].

Step-3:1-(5-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,2-dimethyl-1,3,4-oxadiazol-3(2H)-yl)ethanone:A mixture of step-2 intermediate (800 mg, 2.05 mmol) and pyridine (0.33mL, 4.1 mmol) in acetic anhydride (8 mL) was stirred at 140° C. for 3 h.The reaction was then cooled to room temperature and the solvent wasevaporated under vacuum. The crude product was purified by flash columnchromatography (silica gel, ethyl acetate-hexanes system as eluent) toafford 250 mg (28%) of the title compound as white solid. ¹HNMR (400MHz, DMSO-d₆) δ 8.76 (d, J=2.0 Hz, 1H), 8.36 (dd, J=2.0 & 8.0 Hz, 1H),7.88 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 2.21 (s, 3H), 1.81 (s, 6H); ESI-MS(m/z) 432, 434[(MH)⁺, Br^(79,81)].

Intermediate-82-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,4-dimethyl-4,5-dihydrooxazole

Step-1:1-(5-Bromopyridin-2-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide:To (0° C.) cooled solution of1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylicacid (500 mg, 1.48 mmol), in DCM (20 mL) was added oxalyl chloride (391μL, 4.46 mmol) followed by catalytic amount of DMF. The resultingmixture was stirred at room temperature for 3 h. The solvent and excessof oxalyl chloride was then removed under vacuum and the resultingresidue was dissloved in DCM (10 mL). A solution of2-amino-2-methylpropan-1-ol (0.35 mL, 3.72 mmol) in DCM (5 mL) was thenadded to the above solution drop-wise at 0° C. and the resulting mixturewas warmed to room temperature and then continued stirring at the sametemperature for 18 h. Water (10 mL) was added to the above reactionfollowed by DCM (20 mL). The layers were separated and the aqueous layerwas extracted with DCM (3×10 mL). The combined organic layers werewashed with bine (10 mL), dried (anhydrous Na₂SO₄) and filtered. Thefiltrate was rotary evaporated and the crude product was purified byflash column chromatography to afford 600 mg (99%) of the title compoundas white solid. ¹HNMR (400 MHz, CDCl₃) δ 8.61 (d, J=2.0 Hz, 1H), 8.04(dd, J=2.0 & 8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.37 (s, 1H), 6.96 (s,1H, D₂O exchangeable), 3.73 (s, 2H), 1.44 (s, 6H); ESI-MS (m/z) 407, 409[(MH)⁺, Br^(79,81)].

Step-2:2-(1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,4-dimethyl-4,5-dihydrooxazole:To a stirred solution of step-1 intermediate (600 mg, 1.47 mmol) in DCM(15 mL) at room temperature was added thionyl chloride (215 μL, 2.95mmol) drop-wise and the resulting mixture was then stirred at roomtemperature for 24 h. The reaction was then cooled to 0° C., dilutedwith water (20 mL) and the layers were separated. The aqueous layer wasextracted with DCM (10 mL). The combined organic layers were washed withbrine (10 mL), dried (Na₂SO₄) and filtered. The filtrate was rotaryevaporated and the crude product was purified by flash columnchromatography (silica gel, ethyl acetate-hexanes system as eluent) toafford 310 mg (54%) of the title compound as white solid. ¹HNMR (400MHz, CDCl₃) δ 8.57 (d, J=2.0 Hz, 1H), 8.00 (dd, J=2.0 & 8.0 Hz, 1H),7.89 (d, J=8.0 Hz, 1H), 7.38 (s, 1H), 4.20 (s, 2H), 1.43 (s, 6H); ESI-MS(m/z) 389, 391 [(MH)⁺, Br^(79,81)]

Intermediate-95-(1-(5-Bromopyridin-2-yl)-3-cyclopropyl-1H-pyrazol-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one

Step-1: Ethyl 4-cyclopropyl-2,4-dioxobutanoate: The title compound wasprepared by reacting 1-cyclopropylethanone with diethyl oxalate byfollowing the procedure described in US20120115903.

Step-2: Ethyl 4-cyclopropyl-2-(methoxyimino)-4-oxobutanoate: The titlecompound was prepared by reacting ethyl 4-cyclopropyl-2,4-dioxobutanoatewith O-methylhydroxylamine hydrochloride in ethanol-water (5:1) byfollowing the procedure described in WO2012022487.

Step-3: Ethyl1-(5-Bromopyridin-2-yl)-3-cyclopropyl-1H-pyrazole-5-carboxylate: To astirred solution of ethyl 4-cyclopropyl-2-(methoxyimino)-4-oxobutanoate(420 mg, 1.97 mmol) in acetic acid:2-methoxyethanol (6 mL, 2:1) wasadded 5-bromo-2-hydrazinylpyridine (370 mg, 1.97 mmol) at roomtemperature. The resulting mixture was refluxed for 3 h. The reactionmixture was cooled to room temperature and the solvent was evaporatedunder vacuum. The crude product was purified by flash columnchromatography (silica gel, ethyl acetate-hexanes system) to afford 220mg (33%) of the title compound as pale yellow syrup. ¹HNMR (400 MHz,CDCl₃) δ 8.49 (d, J=2.0 Hz, 1H), 7.95 (dd, J=2.0 & 8.0 Hz, 1H), 7.58 (d,J=8.0 Hz, 1H), 6.56 (s, 1H), 4.30 (q, J=7.0 Hz, 2H), 2.04-1.98 (m, 1H),1.29 (t, J=7.0 Hz, 3H), 1.02-0.97 (m, 2H), 0.83-0.79 (m, 2H); ESI-MS(m/z) 336, 338 [(MH)⁺, Br^(79,81)].

Step-4:5-(1-(5-Bromopyridin-2-yl)-3-cyclopropyl-1H-pyrazol-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one:The title compound was prepared from step-3 intermediate by followingthe procedure sequentially as described in step-4, step-5 and step-6 ofintermediate 1. ¹HNMR (400 MHz, CDCl₃) δ 8.38 (d, J=2.0 Hz, 1H), 7.93(dd, J=2.0 & 8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 6.54 (s, 1H), 3.51 (s,3H), 2.06-1.99 (m, 1H), 1.06-1.01 (m, 2H), 0.89-0.87 (m, 2H); ESI-MS(m/z) 362, 364 [(MH)⁺, Br^(79,81)].

Intermediate-105-(1-(5-Bromopyridin-2-yl)-5-cyclopropyl-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one

Step-1: Ethyl1-(5-bromopyridin-2-yl)-5-cyclopropyl-1H-pyrazole-3-carboxylate: To astirred solution of ethyl 4-cyclopropyl-2,4-dioxobutanoate (0.378 g,2.05 mmol) in acetic acid (5 mL) was added 5-bromo-2-hydrazinylpyridine(386 mg, 2.05 mmol) at room temperature and the resulting mixture wasrefluxed for 2 h. The reaction was then cooled to room temperature andthe solvent was evaporated under vacuum. The crude product was purifiedby flash column chromatography (silica gel, ethyl acetate-hexane systemas eluent) to afford 300 mg (43%) of the title compound as pale yellowsyrup. ¹HNMR (400 MHz, CDCl₃) δ 8.55 (d, J=2.0 Hz, 1H), 7.98 (dd, J=2.0& 8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 6.50 (s, 1H), 4.41 (q, J=7.0 Hz,2H), 2.70-2.64 (m, 1H), 1.40 (t, J=7.0 Hz, 3H), 1.05-1.00 (m, 2H),0.75-0.71 (m, 2H); ESI-MS (m/z) 336, 338 [(MH)⁺ Br^(79,81)].

Step-2:5-(1-(5-Bromopyridin-2-yl)-5-cyclopropyl-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one:The title compound was prepared from step-1 intermediate by followingthe procedure sequentially as described in step-4, step-5 and step-6 ofintermediate-1. ¹HNMR (400 MHz, CDCl₃) δ 8.55 (d, J=2.0 Hz, 1H), 7.99(dd, J=2.0 & 8.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 6.41 (s, 1H), 3.55 (s,3H), 2.80-2.73 (m, 1H), 1.09-1.03 (m, 2H), 0.77-0.74 (m, 2H); ESI-MS(m/z) 362, 364 [(MH)⁺, Br^(79,81)].

Intermediate-115-(1-(5-Bromopyridin-2-yl)-5-methyl-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one

Step-1:Ethyl-1-(5-bromopyridin-2-yl)-5-methyl-1H-pyrazole-3-carboxylate: To astirred solution of 5-bromo-2-hydrazinylpyridine (16.6 g, 89.0 mmol), inethanol (5 mL) and acetic acid (10 mL) was added ethyl2,4-dioxopentanoate (14.0 g, 89.0 mmol) drop-wise at 0° C. and theresulting mixture was stirred at 100° C. for 2 h. The reaction mixturewas then cooled to room temperature and the solvent was evaporated undervacuum. The residue was diluted with water (50 mL) followed by ethylacetate (100 mL). The layers were separated and the aqueous layer wasextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with brine (100 mL), dried (Na₂SO₄) and filtered. Thefiltrate was rotary evaporated and the crude product was purified byflash column chromatography (silica gel, ethyl acetate-hexanes system aseluent) to afford 2.60 g (10%) of the title compound as white solid.¹HNMR (400 MHz, CDCl₃) δ 8.51-8.50 (m, 1H), 7.96-7.93 (m, 2H), 6.71 (s,1H), 4.41 (q, J=7.0 Hz, 2H), 2.67 (s, 3H), 1.41 (t, J=7.0 Hz, 3H);ESI-MS (m/z) 310, 312 [(MH)⁺, Br^(79,81)].

Step-2:5-(1-(5-Bromopyridin-2-yl)-5-methyl-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one:The title compound was prepared from step-1 intermediate by followingthe procedure sequentially described in step-4, step-5 and step-6 ofIntermediate-1. ¹HNMR (400 MHz, CDCl₃) δ 8.53-8.52 (m, 1H), 7.98-7.93(m, 2H), 6.62 (s, 1H), 3.53 (s, 3H), 2.72 (s, 3H); ESI-MS (m/z) 336, 338[(MH)⁺, Br^(79,81)]

Intermediate-12 Methyl3-(1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate

Step-1:1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbaldehyde:To a stirred solution of1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylicacid (6.20 g, 18.45 mmol), in DMF (50 mL) was successively added EDC.HCl(4.24 g, 22.14 mmol), HOBT (3.11 g, 20.29 mmol),N,O-dimethylhydroxylamine hydrochloride (2.70 g, 27.7 mmol) andtriethylamine (5.14 mL, 36.9 mmol). After stirring the reaction mixtureat 65° C. for 12 h, the reaction was cooled to RT. Water (60 mL) wasadded to the above reaction followed by ethyl acetate (100 mL). Thelayers were separated and aqueous layer was extracted with ethyl acetate(3×100 mL). The combined organic layers were washed with water (100 mL),brine (100 mL), dried (Na₂SO₄) and filtered. The filtrate was rotaryevaporated and the crude product was purified by flash columnchromatography (silica gel, ethyl acetate-hexanes system as eluent) toafford 4.20 g (60%) of the1-(5-bromopyridin-2-yl)-N-methoxy-N-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamideas white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 8.74 (d, J=2.5 Hz, 1H), 8.37(dd, J=2.5 & 8.5 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.50 (s, 1H), 3.77 (s,3H), 3.34 (s, 3H); ESI-MS (m/z) 379, 381 [(MH)⁺, Br^(79,81)].

To a −78° C. cooled and stirred solution of1-(5-Bromopyridin-2-yl)-N-methoxy-N-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide(4.40 g, 11.61 mmol) in THF (35 mL) was added DIBAL-H (1M, 29.9 mL, 29.9mmol) over a period of 30 min. Reaction was quenched at the sametemperature with hydrochloric acid (10%) and diluted with ethyl acetate(100 mL). The mixture was stirred at room temperature for 2 h and thenthe layers were separated. The aqueous layer was extracted with ethylacetate (2×100 mL). The combined organic layers were washed with brine(100 mL), dried (Na₂SO₄) and filtered. The filtrate was evaporated andthe crude product was purified by flash column chromatography to afford2.60 g (70%) of the title compound as white solid. ¹HNMR (400 MHz,CDCl₃) δ 10.07 (s, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.08 (dd, J=2.0 & 8.0Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.37 (s, 1H); ESI-MS (m/z) 320, 322[(MH)⁺, Br^(79,81)].

Step-2:1-(5-Bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbaldehydeoxime: To a (0° C.) cooled solution of1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbaldehyde(2.60 g, 8.12 mmol) in methanol (30 mL) was added a solution ofhydroxylamine hydrochloride (0.847 g, 12.19 mmol) in water (5 mL)followed by a solution of sodium carbonate (0.517 g, 4.87 mmol) in water(2 mL). The reaction mixture was warmed to room temperature and thenstirred for 1 h. The reaction mixture was diluted with water (20 mL) anddiluted with ethyl acetate (100 mL). The layers were separated and theaqueous layer was extracted with ethyl acetate (2×50 mL). The combinedorganic layers were washed with brine (50 mL), dried (Na₂SO₄) andfiltered. The filtrate was concentrated under vacuum to afford 2.60 g(96%) as white solid. ¹HNMR (400 MHz, CDCl₃) δ 8.57 (d, J=2.0 Hz, 1H),8.23 (s, 1H), 7.98 (dd, J=2.0 & 8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H),7.67 (s, 1H), 7.19 (s, 1H), ESI-MS (m/z) 335, 337 [(MH)⁺, Br^(79,81)].

Step-3: Methyl3-(1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate:To a stirred solution of step-2 intermediate (3.0 g, 8.95 mmol) inTHF(100 mL) was added NCS (1.79 g, 13.43 mmol) and pyridine (434 μL,5.37 mmol) at 0° C. and then stirred at 60° C. for 3 h. The reaction wasthen cooled back down to 0° C., methyl methacrylate (1.43 mL, 13.43mmol) and triethylamine (2.49 mL, 17.91 mmol) were added sequentially tothe above mixture and the resulting mixture was stirred at 45° C. for 6h. The reaction mixture was cooled to room temperature and then dilutedwith water (50 mL) followed by ethyl acetate (100 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (2×50mL). The combined organic layers were washed with brine (50 mL), dried(Na₂SO₄) and filtered. The filtrate was rotary evaporated and the crudeproduct was purified by flash column chromatography (silica gel, ethylacetate-hexanes system as eluent) to afford 2.0 g (51%) of the titlecompound as white solid. ¹HNMR (400 MHz, CDCl₃) δ 8.58 (d, J=2.0 Hz,1H), 8.01-7.98 (dd, J=2.0 & 8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.32(s, 1H), 4.00 (d, J=17.0 Hz, 1H), 3.81 (s, 3H), 3.36 (d, J=17.0 Hz, 1H),1.74 (s, 3H); ESI-MS (m/z) 433, 435 [(MH)⁺, Br^(79,81)].

Intermediate-13a1-(5-Bromopyridin-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxylic acid AndIntermediate-13b1-(5-Bromopyridin-2-yl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylic acid

Step-1: Ethyl 4-(furan-2-yl)-2,4-dioxobutanoate: To a (0° C.) cooled andstirred suspension of sodium hydride (60% suspension in mineral oil,5.45 g, 136 mmol) in THF (100 mL) was added drop-wise a solution ofdiethyl oxalate (12.4 mL, 91 mmol) over a period of 30 min. Theresulting mixture was then warmed to room temperature and then continuedstirring for 30 min at the same temperature. A solution of1-(furan-2-yl)ethanone (5.0 g, 45.4 mmol) in THF (25 mL) was then addedto the above mixture at room temperature and the resulting mixture wasslowly warmed to 50° C. and continued stirring at the same temperaturefor 5 h. The reaction mixture was cooled down to room temperature andthen quenched with aqueous hydrochloric acid (10%, 10 mL) followed bythe addition of water (50 mL) and ethyl acetate (100 mL). The layerswere separated and the aqueous layer was extracted with ethyl acetate(2×100 mL). The combined organic layers were washed with brine (100 mL),dried (Na₂SO₄) and filtered. The filtrate was rotary evaporated toafford 9.54 g (100%) of the title compound as semisolid. ESI-MS (m/z)211 [(MH)⁺

Step-2: 1-(5-Bromopyridin-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxylicacid and 1-(5-Bromopyridin-2-yl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylicacid: A mixture of ethyl 4-(furan-2-yl)-2,4-dioxobutanoate (1.0 g, 4.76mmol) and 5-bromo-2-hydrazinylpyridine (895 mg, 4.76 mmol) in aceticacid (6 mL) and ethanol (6 mL) was heated at 100° C. for 1 h. Thereaction mixture was cooled to room temperature and the solvent wasevaporated under vacuum. The crude product was purified by flash columnchromatography to afford 60 mg (4%) of intermediate 13a and 200 mg (12%)of the intermediate 13b as white solids.

Intermediate-13a1-(5-Bromopyridin-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxylic acid

¹HNMR (400 MHz, DMSO-d₆) δ3.25 (s, 1H, D₂O exchangeable), 8.67 (d, J=2.0Hz, 1H), 8.35 (dd, J=8.0 & 2.0 Hz, 1H), 7.76-7.72 (m, 2H), 7.17 (s, 1H),6.67-6.66 (m, 1H), 6.56-6.55 (m, 1H); ESI-MS (m/z) 334, 336 [(MH)⁺,Br^(79,81)].

Intermediate-13b1-(5-Bromopyridin-2-yl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylic acid

¹HNMR (400 MHz, DMSO-d₆) δ3.68 (s, 1H, D₂O exchangeable), 8.66 (d, J=2.0Hz, 1H), 8.35 (dd, J=8.0 & 2.0 Hz, 1H), 7.80-7.74 (m, 2H), 7.28 (s, 1H),6.99-6.98 (m, 1H), 6.64-6.63 (m, 1H); ESI-MS (m/z) 334, 336 [(MH)⁺,Br^(79,81)].

Intermediate-145-(1-(5-Bromopyridin-2-yl)-5-(difluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one

Step-1:1-(5-Bromopyridin-2-yl)-3-(furan-2-yl)-N-methoxy-N-methyl-1H-pyrazole-5-carboxamide:To a stirred solution of1-(5-bromopyridin-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carboxylic acid(500 mg, 1.49 mmol) in THF (10 mL) was successively added EDC.HCl (430mg, 2.24 mmol), HOBT (344 mg, 2.24 mmol), N,O-dimethylhydroxylaminehydrochloride (219 mg, 2.24 mmol) and triethylamine 417 μL, 2.99 mmol).The resulting mixture was stirred at room temperature for 16 h. Thereaction was then diluted with water (10 mL) followed by ethyl acetate(10 mL). The layers were separated and the aqueous layer was extractedwith ethyl acetate (3×25 mL). The combined organic layers were washedwith brine (20 mL), dried (Na₂SO₄) and filtered. The filtrate was rotaryevaporated and the crude product was purified by flash columnchromatography (silica gel, ethyl acetate-hexanes system as eluent) toafford 300 mg (7%) of the desired product as white solid. ¹HNMR (400MHz, CDCl₃) δ 8.01 (d, J=2.0 Hz, 1H), 7.96-7.89 (m, 2H), 7.53-7.50 (m,1H), 6.83-6.82 (m, 2H), 6.53-6.52 (m, 1H), 3.48 (s, 3H), 3.36 (s, 3H);(ESI-MS (m/z) 377, 379 [(MH)⁺, Br^(79,81)]

Step-2:1-(5-Bromopyridin-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carbaldehyde: To a−78° C. cooled and stirred solution of step-1 intermediate (10.0 g, 26.5mmol) in THF (40 mL) was added drop-wise DIBAL-H (1M in THF, 53.0 mL,53.0 mmol) over a period of 30 min. The reaction was gradually warmed toroom temperature and stirred overnight. The reaction was then cooled to0° C. and quenched with aqueous hydrochloric acid (10%, 50 mL) followedby the addition of water (50 mL) and ethyl acetate (100 mL). The layerswere separated and the aqueous layer was extracted with ethyl acetate(2×100 mL). The combined organic layers were washed with brine (100 mL),dried (Na₂SO₄) and filtered. The filtrate was rotary evaporated and thecrude product was purified by flash column chromatography to afford 1.50g (17%) of the title compound as white solid. ¹HNMR (400 MHz, DMSO-d₆) δ10.43 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.34 (dd, J=8.0 & 2.0 Hz, 1H),7.93 (d, J=8.0 Hz, 1H), 7.84-7.83 (m, 1H), 7.44 (s, 1H), 7.08-7.07 (m,1H), 6.67-6.65 (m, 1H). (ESI-MS (m/z) 318, 320 [(MH)⁺, Br^(79,81)]

Step-3:5-Bromo-2-(5-(difluoromethyl)-3-(furan-2-yl)-1H-pyrazol-1-yl)pyridine:To a cooled (−35° C.) and stirred solution of step-2 intermediate (4.0g, 12.57 mmol) in DCM (100 mL) was added DAST (4.15 mL, 31.4 mmol)drop-wise and the reaction was gradually warmed to room temperature andthen stirred at the same temperature overnight. The reaction mixture wasdiluted with water (50 mL) followed by DCM (50 mL). The layers wereseparated and the aqueous layer was extracted with DCM (2×100 mL). Thecombined organic layers were washed with brine (100 mL), dried (Na₂SO₄)and filtered. The filtrate was rotary evaporated and the crude productwas purified by flash column chromatography to afford 2.70 g (63%) ofthe title compound as white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 8.64 (d,J=2.0 Hz, 1H), 8.28 (dd, J=8.0 & 2.0 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H),7.84-7.83 (m, 1H), 7.77 (t, J=50 Hz, 1H), 7.29 (s, 1H), 7.07-7.06 (m,1H), 6.66-6.65 (m, 1H); (ESI-MS (m/z) 340, 342 [(MH)⁺, Br^(79,81)].

Step-4:5-(1-(5-Bromopyridin-2-yl)-5-(difluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one:The title compound was prepared from step-3 intermediate by followingthe similar procedure sequentially as described in step-4, step-5 andstep-6 of intermediate-1. ¹HNMR (400 MHz, Cd₃CN) δ 8.60 (d, J=2.0 Hz,1H), 8.17 (dd, J=8.0 & 2.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.72 (t,J=50 Hz, 1H), 7.28 (s, 1H), 3.45 (s, 3H); (ESI-MS (m/z) 372, 374 [(MH)⁺,Br^(79,81)].

Intermediate-155-(1-(5-Bromopyridin-2-yl)-3-(difluoromethyl)-1H-pyrazol-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one

The title compound was prepared from Intermediate 13b by following thesimilar procedure as described in Intermediate-14. ¹HNMR (400 MHz,DMSO-d₆) δ 8.66 (d, J=2.0 Hz, 1H), 8.36 (dd, J=8.0 &2.0 Hz, 1H), 7.87(d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.23 (t, J=50 Hz, 1H), 3.40 (s, 3H);(ESI-MS (m/z) 372, 374 [(MH)⁺, Br^(79,81)].

Intermediate-165-(1-(5-Bromopyridin-2-yl)-5-(fluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one

Step-1:(1-(5-Bromopyridin-2-yl)-3-(furan-2-yl)-1H-pyrazol-5-yl)methanol: To astirred solution of1-(5-bromopyridin-2-yl)-3-(furan-2-yl)-1H-pyrazole-5-carbaldehyde (5.0g, 15.72 mmol) in THF (40 mL) was added borane-THF complex (1M, 31.4 mL,31.4 mmol) drop-wise at 0° C. over a period of 15 min. The reaction wasgradually warmed to room temperature and then stirred at the sametemperature for 2 h. The reaction was cooled to 0° C. and then quenchedwith ice cold water (10 mL) followed by the addition of ethyl acetate(50 mL). The layers were separated and the aqueous layer was extractedwith ethyl acetate (2×100 mL). The combined organic layers were washedwith brine (50 mL), dried (Na₂SO₄) and filtered. The filtrate was rotaryevaporated and the crude product was purified by flash columnchromatography (silica gel, ethyl acetate-hexanes system as eluent) toafford 2.0 g (40%) of the title compound as white solid. ¹HNMR (400 MHz,CDCl₃) δ 8.48 (d, J=2.0 Hz, 1H), 8.0 (d, J=8.0 Hz, 1H), 8.00 (dd, J=8.0& 2.0 Hz, 1H), 7.53-7.51 (m, 1H), 6.79-6.78 (m, 1H), 6.65 (s, 1H),6.52-6.50 (m, 1H), 5.28 (s, 1H), 4.76 (s, 2H); ESI-MS (m/z) 320, 322[(MH)⁺, Br^(79,81)]

Step-2:5-Bromo-2-(5-(fluoromethyl)-3-(furan-2-yl)-1H-pyrazol-1-yl)pyridine: Toa (−78° C.) cooled and stirred solution of step-1 intermediate (2.0 g,6.25 mmol) in DCM (30 mL) was drop-wise added DAST (1.65 mL, 12.49 mmol)and the reaction was then warmed to −40° C. and then stirred for 2 h atthat temperature. The reaction was diluted with water (30 mL) at −40° C.followed by the addition of DCM (50 mL). The layers were separated andthe aqueous layer was extracted with DCM (2×50 mL). The combined organiclayers were washed with brine (50 mL), dried (Na₂SO₄) and filtered. Thefiltrate was rotary evaporated and the crude product was purified byflash column chromatography to afford 1.10 g (54%) of the title compoundas white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 8.62 (d, J=2.0 Hz, 1H), 8.25(dd, J=8.0 & 2.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.81 (m, 1H),7.00-6.99 (m, 1H), 6.97 (s, 1H), 6.65-6.63 (m, 1H), 5.93 (d, J=50 Hz,2H); (ESI-MS (m/z) 322, 324 [(MH)⁺, Br^(79,81)].

Intermediate-17 5-Hydrazinyl-2-nitropyridine hydrochloride

Step-1: tert-butyl 1-(6-nitropyridin-3-yl)hydrazinecarboxylate: To anitrogen purged solution of 5-bromo-2-nitropyridine (50 g, 246 mmol) andtert-butyl hydrazinecarboxylate (26.0 g, 197 mmol) in toluene (500 mL)in a sealed tube, cesium carbonate (93.0 g, 286 mmol), dppf (20.48 g,36.9 mmol) and Pd₂(dba)₃ (15.79 g, 17.24 mmol) were sequentially added.The resulting mixture was thoroughly deoxygenated by flushing nitrogengas for 15 min and the resulting mixture was stirred at 100° C. for 5 h.The reaction mixture was cooled to room temperature and then filteredthrough celite. The filtrate was rotary evaporated and the crude productwas purified by flash column chromatography (silica gel, ethylacetate-hexanes system as eluent) to afford 23.0 g (38%) of the titlecompound as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ 9.0 (d, J=2.5 Hz,1H), 8.36 (dd, J=2.5 & 8.5 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 4.47 (s, 2H,D₂O exchangeable) 1.61 (s, 9H); GCMS (m/z) 154 (M-Boc)⁺

Step-2: 5-Hydrazinyl-2-nitropyridine hydrochloride: To (0° C.) cooledsolution of tert-butyl 1-(6-nitropyridin-3-yl)hydrazinecarboxylate (5.0g, 19.67 mmol) in dry 1,4-dioxane (250 mL) was added aqueoushydrochloric acid (2N, 98 mL). After stirring for 16 h at 25° C., thesolvent was evaporated under vacuum. The residue was triturated withhexane and dried under vacuum to afford 2.70 g (89%) of the titlecompound as pink solid. ¹HNMR (400 MHz, DMSO-d₆) δ10.75 (brs, 2H, D₂Oexchangeable), 9.75 (s, 1H, D₂O exchangeable), 8.32 (d, J=8.5 Hz, 1H),8.21 (d, J=2.5 Hz, 1H), 7.55(dd, J=2.5 & 8.5 Hz, 1H).

Intermediate-185-(1-(6-Aminopyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one

Step-1:3-(Furan-2-yl)-1-(6-nitropyridin-3-yl)-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-ol:To a stirred solution of Intermediate-17, (17.0 g, 89 mmol) in ethanol(50 mL) was added DIPEA (31.2 mL, 178 mmol) at 0° C. and stirred for 30min. The resulting mixture was added drop-wise to a 0° C. cooledsolution of 1,1,1-trifluoro-4-(furan-2-yl)-4-methoxybut-3-en-2-one (23.5g, 107 mmol) in ethanol (20 mL). The resulting mixture was warmed toroom temperature and then stirred at 45° C. overnight. The solvent wasremoved under reduced pressure and the residue was purified by flashcolumn chromatography (silica gel, 30% ethyl acetate-hexanes system aseluent) to afford 12.0 g (30%) of the title compound as a pink solid.¹HNMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H, D₂O exchangeable), 8.65 (d,J=2.5 Hz, 1H), 8.34 (d, J=8.5 Hz, 1H), 8.02 (dd, J=2.5 & 8.5 Hz, 1H),7.94 (d, J=1.5 Hz, 1H), 7.12 (d, J=3.0 Hz, 1H), 6.72 (dd, J=1.5 & 3.0Hz, 1H), 4.00 (d, J=19.0 Hz, 1H), 3.66 (d, J=19.0 Hz, 1H); ESI-MS (m/z)343 (MH)⁺.

Step-2:5-(3-(Furan-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2-nitropyridine:To a (0° C.) cooled solution of step-1 intermediate (1.50 g, 4.38 mmol)in DCM (15 mL) was added SOCl₂ (0.70 mL, 9.64 mmol). After stirring for15 min at 0° C., pyridine (0.88 mL, 10.9 mmol) was added at the sametemperature and the resulting mixture was stirred for 30 min at 0° C.The solvent was removed under reduced pressure and the residue wasdissolved in ice cooled water (30 mL) and ethyl acetate (25 mL). Thelayers were separated and the aqueous layer was extracted with ethylacetate (2×50 mL). The combined organic layers were washed withsaturated aqueous NaHCO₃ solution (50 mL), dried (Na₂SO₄) and filtered.The filtrate was concentrated under vacuum and the crude product waspurified by flash column chromatography (silica gel, ethylacetate-hexanes system as eluent) to afford 1.0 g (74%) of the titlecompound as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 8.94 (d, J=2.5 Hz,1H), 8.45 (d, J=8.5 Hz, 1H), 8.30 (dd, J=2.5 & 8.5 Hz, 1H), 7.56 (d,J=1.5 Hz, 1H), 7.27 (s, 1H), 6.89 (d, J=3.0 Hz, 1H), 6.56 (dd, J=1.5 &3.0 Hz, 1H); ESI-MS (m/z) 325 (MH)⁺.

Step-3:1-(6-Nitropyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylicacid: The title compound was prepared by reacting step-2 intermediate(4.0 g, 12.34 mmol) with potassium permanganate (13.0 g, 83 mmol) byfollowing the similar procedure as described in Step-2 of Intermediate-1to afford 3.0 g (80%) of the desired product as a white solid. ¹HNMR(400 MHz, DMSO-d₆) δ 8.99 (d, J=1.5 Hz, 1H), 8.60-8.57 (m, 2H), 7.71 (s,1H); ESI-MS (m/z) 302 (MH)⁺.

Step-4: tert-Butyl2-(1-(6-nitropyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbonyl)hydrazinecarboxylate: To a stirred solution of step-3 intermediate (2.50g, 8.27 mmol) in DCM (25 mL) was successively added EDC.HCl (2.37 g,12.41 mmol), HOBT (0.634 g, 4.14 mmol) and tert-butylhydrazinecarboxylate (1.093 g, 8.27 mmol). After stirring at room temperature for6 h, the reaction mixture was diluted with water (10 mL) anddichloromethane (30 mL). The layers were separated and aqueous layer wasextracted with dichloromethane (3×20 mL). The combined organic layerswere washed with brine (50 mL), dried (Na₂SO₄) and filtered. Thefiltrate was rotary evaporated and the crude product was purified byflash column chromatography to afford 2.0 g (58%) of the title compoundas a white solid. ¹HNMR (400 MHz, CDCl₃) δ 8.89 (d, J=2.5 Hz, 1H), 8.53(s, 1H, D₂O exchangeable), 8.49 (d, J=8.5 Hz, 1H), 8.27 (dd, J=2.5 & 8.5Hz, 1H), 7.85 (s, 1H, D₂O exchangeable), 7.51 (s, 1H), 1.51 (s, 9H);ESI-MS (m/z) 317 (M-Boc)⁺.

Step-5:1-(6-Nitropyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbohydrazide:To a (0° C.) cooled solution of step-4 intermediate (2.0 g, 4.80 mmol)in dichloromethane (25 mL) was added drop-wise trifluoroacetic acid(3.70 mL, 48.0 mmol). After stirring the reaction mixture at roomtemperature for 18 h, the solvent was evaporated under reduced pressure.The crude product was triturated with diethyl ether to obtain 1.32 g(87%) of the title compound as semi solid. The residue was used for nextstep without further purification. ESI-MS (m/z) 317 (MH)⁺.

Step-6:3-Methyl-5-(1-(6-nitropyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2(3H)-one:The title compound was prepared from step-5 intermediate by followingthe similar procedure sequentially as described in Step-5 and Step-6 ofIntermediate-1. ¹HNMR (400 MHz, CDCl₃) δ 8.91 (d, J=2.5 Hz, 1H), 8.48(d, J=8.5 Hz, 1H), 8.31(dd, J=2.5 & 8.5 Hz, 1H), 7.37 (s, 1H), 3.53 (s,3H); ESI-MS (m/z) 398 (M+acetonitrile).

Step-7:5-(1-(6-Aminopyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one:To a 0° C. cooled and stirred solution of Step-6 intermediate (500 mg,1.40 mmol) in ethanol (10 mL) and hydrochloric acid (1M, 0.5 mL) wasadded iron powder (800 mg, 14 mmol, 10 eq) portion-wise. The resultingmixture was then stirred at 95° C. for 2 h. The reaction was then cooleddown to 0° C., poured in ice water and basified with aqueous ammoniasolution followed by the addition of ethyl acetate (20 mL). The layerswere separated and the aqueous layer was extracted with ethyl acetate(2×25 mL). The combined organic layers were washed with brine (50 mL),dried (Na₂SO₄) and filtered. The filtrate was rotary evaporated toafford 400 mg (87%) of the title product as a white solid. ¹HNMR (400MHz, DMSO-d₆) ¹HNMR (400 MHz, CDCl₃) δ 8.06 (d, J=2.0 Hz, 1H), 7.62 (s,1H), 7.55 (dd, J=2.5, 8.5 Hz, 1H), 6.61 (s, 2H, D₂O exchangeable), 6.55(d, J=8.5 Hz, 1H), 3.41 (s, 3H); ESI-MS (m/z) 327 (MH)⁺.

EXAMPLES Example-12,6-Difluoro-N-(6-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide

To a nitrogen purged solution of Intermediate-1 (200 mg, 0.51 mmol) indioxane (5 mL), was added potassium phosphate (268 mg, 1.54 mmol),2,6-difluorobenzamide (161 mg, 1.02 mmol), trans1,2-diaminocyclohexane(25 μL, 0.205 mmol) and copper(I) iodide (39 mg, 0.205 mmol)sequentially. The resulting mixture was thoroughly deoxygenated bypurging nitrogen gas for 15 min and then the resulting mixture wasstirred at 110° C. for (30 min×2) in a microwave (Biotage). The reactionmixture was cooled down to room temperature and then filtered throughcelite. The filtrate was evaporated and the crude product was purifiedby flash column chromatography (silica gel, 30% ethyl acetate-hexanessystem as eluent) to afford 45 mg (18%) of the desired product as whitesolid. ¹HNMR (400 MHz, CDCl₃) δ 8.55 (d, J=2.5 Hz, 1H), 8.50 (dd, J=2.5& 8.5 Hz, 1H), 7.97 (s, 1H, D₂O exchangeable), 7.91 (d, J=8.5 Hz, 1H),7.52-7.48 (m, 1H), 7.12 (s, 1H), 7.06 (t, J=8.5 Hz, 2H), 3.49 (s, 3H);ESI-MS (m/z) 467 (MH)⁺.

Example-22-Fluoro-6-methyl-N-(6-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide

The title compound was prepared by following the similar procedure asdescribed in Example-1 by using Intermediate-1 and2-fluoro-6-methylbenzamide. ¹HNMR (400 MHz, CDCl₃) δ 8.55 (s, 1H, D₂Oexchangeable), 8.50 (d, J=8.5 Hz, 1H), 7.91-7.88 (m, 2H), 7.38-7.32 (m,1H), 7.12 (s, 1H) 7.10 (d, J=8.0 Hz, 1H), 7.01 (t, J=8.0 Hz, 1H), 3.49(s, 3H), 2.50 (s, 3H); ESI-MS (m/z) 463 (MH)⁺.

Example-35-(3-Cyclopropyl-1-(5-((2,6-difluorobenzyl)amino)pyridin-2-yl)-1H-pyrazol-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one

In a microwave vial containing toluene (10 mL) and cesium carbonate (360mg, 1.104 mmol) was purged nitrogen gas for 30 min and thenIntermediate-9 (200 mg, 0.552 mmol), (2,6-difluorophenyl)methanamine (95mg, 0.663 mmol) and BINAP (34.4 mg, 0.055 mmol) were sequentially added.The resulting mixture was thoroughly deoxygenated by purging nitrogengas for another 15 min and then Pd₂(dba)₃ (37.9 mg, 0.041 mmol) wasadded to the above mixture. Microwave vial was then sealed and kept inmicrowave reactor and stirred at 125° C. for 1 h. The reaction mixturewas cooled to room temperature and filtered through celite. The filtratewas rotary evaporated and the crude product was purified by flash columnchromatography (silica gel, ethyl acetate-hexanes system as eluent) toafford 12 mg (5%) of the title compound as white solid. ¹HNMR (400 MHz,DMSO-d₆) δ 7.78 (s, 1H), 7.47-7.42 (m, 2H), 7.22-7.13 (m, 3H), 6.71 (s,1H), 6.11 (brs, 1H, D₂O exchangeable), 4.34 (d, J=4.0 Hz, 2H), 3.34 (s,3H), 2.10-1.90 (m, 1H), 0.95-0.93 (m, 2H), 0.80-0.76 (m, 2H); ESI-MS(m/z) 425 (MH)⁺

The below Examples 4 to 7 given in Table-1 were prepared by followingthe similar procedure as described in Example-3 by using appropriateintermediate of Intermediate-12, Intermediate-15 or Intermediate-16 andappropriate amine or amide Intermediate.

TABLE 1 Example No: IUPAC name Structure ¹H-NMR/ESI-MS Example-4:N-(6-(3- (Difluoromethyl)-5-(4- methyl-5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)-1H- pyrazol-1-yl)pyridin-3- yl)-2,6- difluorobenzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.38 (s, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.41(dd, J = 8.0 & 2.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.69-7.61 (m, 1H),7.40 (s, 1H), 7.31 (t, J = 8.0 Hz, 2H), 7.23 (t, J = 50 Hz, 1H), 3.40(s, 3H); ESI- MS (m/z) 449 (MH)⁺ Example-5: 5-(1-(5- ((2,6-Difluorobenzyl)amino) pyridin-2-yl)-5- (fluoromethyl)-1H-pyrazol-3-yl)-3-methyl- 1,3,4-oxadiazol-2(3H)- one

¹HNMR (400 MHz, DMSO-d₆) δ 7.90 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.48-7.40 (m, 1H), 7.29 (dd, J = 8.0 & 2.0 Hz, 1H), 7.15 (t, J= 8.0 Hz, 2H), 7.01 (s, 1H), 6.70 (t, J = 5.0 Hz, 1H, D₂O exchangeable),5.83 (d, J = 50 Hz, 2H), 4.37 (d, J = 5.0 Hz, 2H), 3.35 (s, 3H); ESI-MS(m/z) 417 (MH)⁺ Example-6: Methyl 3- (1-(5-((2,6- difluorobenzyl)amino)pyridin-2-yl)-5- (trifluoromethyl)-1H- pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole- 5-carboxylate

¹HNMR (400 MHz, DMSO-d₆) δ 7.91 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 8.0Hz, 1H), 7.46-7.42 (m, 1H), 7.40 (s, 1H), 7.25-7.23 (dd, J = 2.0 & 8.0Hz, 1H), 7.15 (t, J = 8.0 Hz, 2H), 6.85 (t, J = 5.0 Hz, 1H, D₂Oexchangeable), 4.36 (d, J = 5.0 Hz, 2H), 3.83 (d, J = 17.0 Hz, 1H), 3.69(s, 3H), 3.44 (d, J = 17.0 Hz, 1H), 1.59 (s, 3H); ESI-MS (m/z) 496 (MH)⁺Example-7: Methyl 3- (1-(5-((2-chloro-6- fluorobenzyl)amino)pyridin-2-yl)-5- (trifluoromethyl)-1H- pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole- 5-carboxylate

¹HNMR (400 MHz, DMSO-d₆) δ 7.59 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.0Hz, 1H), 7.45-7.39 (m, 3H), 7.33-7.26 (m, 2H), 6.75 (t, J = 5.0 Hz, 1H,D₂O exchangeable), 4.42 (d, J = 5.0 Hz, 2H), 3.85 (d, J = 17.0 Hz, 1H),3.71 (s, 3H), 3.46 (d, J = 17.0 Hz, 1H), 1.61 (s, 3H); ESI-MS (m/z) 512,514 [(MH)⁺, Cl^(35,37)]

Example-82,6-Difluoro-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide

To a nitrogen purged solution of Intermediate-2 (2.0 g, 5.13 mmol) indioxane (8 mL) in a microwave vial was added cesium carbonate (3.34 g,10.25 mmol), 2,6-difluorobenzamide (1.05 g, 6.66 mmol) and xantphos (445mg, 0.77 mmol) sequentially. The resulting mixture was thoroughlydeoxygenated by purging nitrogen gas for 15 min and then palladium (II)acetate (115 mg, 0.513 mmol) was added to the above reaction mixture.Microwave vial was sealed and kept in microwave (Biotage) and heated to125° C. and maintained for 1 h. The reaction mixture was cooled to roomtemperature and filtered through celite. The filtrate was evaporated andthe crude product was purified by flash column chromatography (silicagel, 40% ethyl acetate-hexanes system as eluent) to afford 790 mg (33%)of the desired product as white solid. ¹HNMR (400 MHz, CDCl₃) δ 8.65 (d,J=2.5 Hz, 1H), 8.50 (dd, J=2.5 & 8.5 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H),7.90 (s, 1H, D₂O exchangeable), 7.54-7.47 (m, 1H), 7.28 (s, 1H), 7.07(t, J=8.5 Hz, 2H), 3.55 (s, 3H); ESI-MS (m/z) 467 (MH)+.

The below Examples 9 to 32 given in Table-2 were prepared by followingthe similar procedure as described in Example-8 by using correspondingIntermediate (Intermediate 2, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15) andappropriate amine or amide Intermediate.

TABLE 2 Example No: IUPAC name Structure ¹H-NMR/ESI-MS Example-9:2-Chloro-6- fluoro-N-(6-(3-(4- methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol- 2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin- 3-yl)benzamide

¹HNMR (400 MHz, CDCl₃) δ 8.65 (d, J = 2.5 Hz, 1H), 8.49 (dd, J = 2.5 &8.5 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.80 (s, 1H, D₂O exchangeable),7.46-7.42 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.17 (t, J =8.0 Hz, 1H), 3.55 (s, 3H); ESI-MS (m/z) 483 (MH)⁺ Example-10: 2-Fluoro-6-methyl-N-(6-(3-(4- methyl-5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)- 1H-pyrazol-1-yl)pyridin- 3-yl)benzamide

¹HNMR (400 MHz, CDCl₃) δ 8.65 (d, J = 2.5 Hz, 1H), 8.49 (dd, J = 2.5 &8.5 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.79 (s, 1H, D₂O exchangeable),7.39-7.34 (m, 1H), 7.28 (s, 1H), 7.12 (d, J = 7.5 Hz 1H) 7.04 (t, J =7.5 Hz, 1H), 3.55 (s, 3H), 2.52 (s, 3H); ESI-MS (m/z) 463 (MH)⁺Example-11: N-(6-(5- (Difluoromethyl)-3-(4- methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol- 2-yl)-1H-pyrazol-1- yl)pyridin-3-yl)-2,6-difluorobenzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.40 (s, 1H, D₂O exchangeable), 8.01 (d, J =2.0 Hz, 1H), 8.03 (dd, J = 8.0 & 2.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H),7.83 (t, J = 50 Hz, 1H), 7.69-7.61 (m, 1H), 7.35 (s, 1H), 7.30 (t, J =8.0 Hz, 2H), 3.43 (s, 3H); ESI-MS (m/z) 449 (MH)⁺ Example-12: 5-(1-(5-((2,6-Difluorobenzyl) amino)pyridin-2-yl)-5- (difluoromethyl)-1H-pyrazol-3-yl)-3-methyl- 1,3,4-oxadiazol-2(3H)- one

¹HNMR (400 MHz, DMSO-d₆) δ 7.91 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 8.0Hz, 1H), 7.67 (t, J = 50 Hz, 1H), 7.48-7.41 (m, 1H), 7.30 (dd, J = 8.0 &2.0 Hz, 1H), 7.24 (s, 1H), 7.15 (t, J = 8.0 Hz, 2H), 6.78 (t, J = 5.0Hz, 1H, D₂O exchangeable), 4.38 (d, J = 5.0 Hz, 2H), 3.41 (s, 3H);ESI-MS (m/z) 435 (MH)⁺ Example-13: 5-(1-(5- ((2,6- Difluorobenzyl)amino)pyridin-2-yl)-3- (difluoromethyl)-1H- pyrazol-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)- one

¹HNMR (400 MHz, CDCl₃) δ 7.87 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.0 Hz,1H), 7.32-7.25 (m, 1H), 7.19 (dd, J = 8.0 & 2.0 Hz, 1H), 7.05 (s, 1H),6.93 (t, J = 8.0 Hz, 2H), 6.76 (t, J = 50 Hz, 1H), 4.50 (s, 2H), 3.48(s, 3H); ESI-MS (m/z) 435 (MH)⁺ Example-14: N-(6-(3-(5,5-Dimethyl-4-oxo-4,5- dihydroisoxazol-3-yl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3- yl)-2,6- difluorobenzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.35 (s, 1H, D₂O exchangeable), 8.82 (d, J =2.5 Hz, 1H), 8.47 (dd, J = 2.5 & 8.5 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H),7.69-7.63 (m, 1H), 7.62 (s, 1H), 7.31 (t, J = 7.5 Hz, 2H) 1.46 (s, 6H);ESI-MS (m/z) 480 (MH)⁺ Example-15: 2-Chloro- N-(6-(3-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol- 3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin- 3-yl)-6-fluorobenzamide

¹HNMR (400 MHz, CDCl₃) δ 8.67 (d, J = 2.5 Hz, 1H), 8.51 (dd, J = 2.5 &8.5 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.95 (s, 1H, D₂O exchangeable),7.50 (s, 1H), 7.43- 7.40 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.15 (t, J =8.0 Hz, 1H), 1.53 (s, 6H); ESI-MS (m/z) 496, 497 [(MH)⁺, Cl^(35,37)]Example-16: 2,6- Difluoro-N-(6-(1′,4′,4′- trimethyl-5′-oxo-5-(trifluoromethyl)-4′,5′- dihydro-1H,1′H-[3,3′- bipyrazol]-1-yl)pyridin-3-yl)benzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.36 (s, 1H, D₂O exchangeable), 8.84 (d, J =2.0 Hz, 1H), 8.41 (dd, J = 2.0 & 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H),7.69-7.61 (m, 1H), 7.53 (s, 1H), 7.31 (t, J = 8.0 Hz, 2H) 3.34 (s, 3H),1.45 (s, 6H); ESI-MS (m/z) 493 (MH)⁺ Example-17: 2-Chloro-6-fluoro-N-(6-(1′,4′,4′- trimethyl-5′-oxo-5- (trifluoromethyl)-4′,5′-dihydro-1H,1′H-[3,3′- bipyrazol]-1-yl)pyridin- 3-yl)benzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.38 (s, 1H, D₂O exchangeable), 8.83 (d, J =2.0 Hz, 1H), 8.42 (dd, J = 2.0 & 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H),7.64-7.58 (m, 1H), 7.53 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H) 7.45 (t, J =8.0 Hz, 1H) 3.34 (s, 3H), 1.45 (s, 6H); ESI-MS (m/z) 509 (MH)⁺Example-18: 2-Fluoro- 6-methyl-N-(6-(1′,4′,4′- trimethyl-5′-oxo-5-(trifluoromethyl)-4′,5′- dihydro-1H,1′H-[3,3′- bipyrazol]-1-yl)pyridin-3-yl)benzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.19 (s, 1H, D₂O exchangeable), 8.84 (d, J =2.0 Hz, 1H), 8.45 (dd, J = 2.0 & 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H),7.52 (s, 1H), 7.46- 7.42 (m, 1H), 7.22-7.18 (m, 2H), 3.34 (s, 3H), 2.36(s, 3H), 1.45 (s, 6H); ESI-MS (m/z) 489 (MH)⁺ Example-19: 2,6-Difluoro-N-(6-(3-(4- methyl-5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)- 1H-pyrazol-1-yl)pyridin- 3-yl)benzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.42 (s, 1H, D₂O exchangeable), 8.85 (d, J =2.0 Hz, 1H), 8.45 (dd, J = 2.0 & 8.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H),7.81 (s, 1H), 7.70- 7.62 (m, 1H), 7.32 (t, J = 8.0 Hz, 2H), 3.52 (s,3H); ESI-MS (m/z) 467 (MH)⁺ Example-20: N-(6-(3-(4-Acetyl-5,5-dimethyl-4,5- dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)- 1H-pyrazol-1-yl)pyridin- 3-yl)-2,6-difluorobenzamide

¹HNMR (400 MHz, CDCl₃) δ 8.63 (d, J = 2.0 Hz, 1H), 8.53 (dd, J = 2.0 &8.0 Hz, 1H), 8.13 (s, 1H, D₂O exchangeable), 7.90 (d, J = 8.0 Hz, 1H),7.53-7.46 (m, 1H), 7.29 (s, 1H), 7.06 (t, J = 8.0 Hz, 2H), 2.31 (s, 3H),1.91 (s, 6H); ESI-MS (m/z) 509 (MH)⁺ Example-21: N-(6-(3-(4,4-Dimethyl-4,5- dihydrooxazol-2-yl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3- yl)-2,6- difluorobenzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.39 (s, 1H, D₂O exchangeable), 8.78 (d, J =2.0 Hz, 1H), 8.46 (dd, J = 2.0 & 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H),7.68-7.63 (m, 1H), 7.54 (s, 1H), 7.31 (t, J = 8.0 Hz, 2H), 4.15 (s, 2H),1.31 (s, 6H); ESI-MS (m/z) 466 (MH)⁺ Example-22: 5-(1-(5-((2,6-Difluorobenzyl) amino)pyridin-2-yl)-5- (trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl- 1,3,4-oxadiazol-2(3H)- one

¹HNMR (400 MHz, CDCl₃) δ 7.97 (d, J = 2.5 Hz, 1H), 7.58 (d, J = 8.5 Hz,1H), 7.31-7.26 (m, 1H), 7.21-7.18 (m, 2H), 6.94 (t, J = 8.0 Hz, 2H),4.51 (s, 2H), 3.53 (s, 3H); ESI-MS (m/z) 453 (MH)⁺ Example-23: 5-(1-(5-((2-Chloro-6- fluorobenzyl)amino) pyridin-2-yl)-5- (trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl- 1,3,4-oxadiazol-2(3H)- one

¹HNMR (400 MHz, CDCl₃) δ 7.97 (d, J = 2.5 Hz, 1H), 7.58 (d, J = 8.5 Hz,1H), 7.30-7.20 (m, 5H), 7.08-7.06 (m, 1H), 4.58 (s, 2H), 3.53 (s, 3H);ESI-MS (m/z) 469, 471 [(MH)⁺, Cl^(35,37)] Example-24: 1′-(5-((2,6-Difluorobenzyl)amino) pyridin-2-yl)-1,4,4- trimethyl-5′-(trifluoromethyl)-1H,1′H- [3,3′-bipyrazol]-5(4H)- one

¹HNMR (400 MHz, DMSO-d₆) δ 7.92 (d, J = 2.5 Hz, 1H), 7.56 (d, J = 8.5Hz, 1H), 7.47-7.42 (m, 1H), 7.41 (s, 1H), 7.28 (dd, J = 2.5 & 8.5 Hz,1H), 7.16 (t, J = 8.0 Hz, 2H), 6.83 (t, J = 5.5 Hz, 1H, D₂Oexchangeable), 4.38 (d, J = 5.5 Hz, 2H), 3.33 (s, 3H), 1.41 (s, 6H);ESI-MS (m/z) 479 (MH)⁺ Example-25: 1′-(5-((2- Chloro-6-fluorobenzyl)amino) pyridin-2-yl)-1,4,4-trimethyl- 5′-(trifluoromethyl)-1H,1′H-[3,3′-bipyrazol]- 5(4H)-one

¹HNMR (400 MHz, DMSO-d₆) δ 7.95 (d, J = 2.5 Hz, 1H), 7.57 (d, J = 8.5Hz, 1H), 7.48-7.39 (m, 2H), 7.41 (s, 1H), 7.33-7.28 (m, 2H), 6.74 (t, J= 5.0 Hz, 1H, D₂O exchangeable), 4.42 (d, J = 5.0 Hz, 2H), 3.33 (s, 3H),1.41 (s, 6H); ESI-MS (m/z) 495, 497 [(MH)⁺, Cl^(35,37)] Example-26:3-(1-(5- ((2,6- Difluorobenzyl)amino) pyridin-2-yl)-5-(trifluoromethyl)-1H- pyrazol-3-yl)-4-methyl- 1,2,4-oxadiazol-5(4H)- one

¹HNMR (400 MHz, DMSO-d₆) δ 7.96 (d, J = 2.0 Hz, 1H), 7.69 (s, 1H), 7.63(d, J = 8.0 Hz, 1H), 7.47-7.41 (m, 1H), 7.28 (dd, J = 2.0 & 8.0 Hz, 1H),7.16 (t, J = 8.0 Hz, 2H), 6.92 (t, J = 5.0 Hz, 1H, D₂O exchangeable),4.39 (d, J = 5.0 Hz, 2H), 3.47 (s, 3H); ESI-MS (m/z) 453 (MH)⁺Example-27: 1-(5-(1-(5- ((2,6- Difluorobenzyl)amino) pyridin-2-yl)-5-(trifluoromethyl)-1H- pyrazol-3-yl)-2,2- dimethyl-1,3,4-oxadiazol-3(2H)- yl)ethanone

¹HNMR (400 MHz, CDCl₃) δ 7.96 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.0 Hz,1H), 7.32-7.28 (m, 1H), 7.21 (s, 1H), 7.17 (dd, J = 2.0 & 8.0 Hz, 1H),6.94 (t, J = 8.0 Hz, 2H), 4.51 (s, 2H), 2.31 (s, 3H), 1.89 (s, 6H);ESI-MS (m/z) 495 (MH)⁺ Example-28: N-(2,6- Difluorobenzyl)-6-(3-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3- amine

¹HNMR (400 MHz, DMSO-d₆) δ 7.93 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.0Hz, 1H), 7.50-7.43 (m, 1H), 7.41 (s, 1H), 7.26 (dd, J = 2.0 & 8.0 Hz,1H), 7.16 (t, J = 8.0 Hz, 2H), 6.82 (t, J = 5.0 Hz, 1H, D₂Oexchangeable), 4.38 (d, J = 5.0 Hz, 2H), 4.12 (s, 2H), 1.29 (s, 6H);ESI-MS (m/z) 452 (MH)⁺ Example-29: N-(6-(5- Cyclopropyl-3-(4-methyl-5-oxo-4,5- dihydro-1,3,4-oxadiazol- 2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6- difluorobenzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.32 (s, 1H, D₂O) δ exchangeable), 8.83 (d,J = 2.0 Hz, 1H), 8.40 (dd, J = 2.0 & 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz,1H), 7.67-7.63 (m, 1H), 7.31 (t, J = 8.0 Hz, 2H), 6.64 (s, 1H), 3.41 (s,3H), 2.67-2.59 (m, 1H), 1.02-0.97 (m, 2H), 0.81-0.77 (m, 2H); ESI-MS(m/z) 439 (MH)⁺ Example-30: N-(6-(3- Cyclopropyl-5-(4- methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol- 2-yl)-1H-pyrazol-1- yl)pyridin-3-yl)-2,6-difluorobenzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.25 (s, 1H, D₂O exchangeable), 8.65 (d, J=2.0 Hz, 1H), 8.32 (dd, J = 2.0 & 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H),7.67-7.60 (m, 1H), 7.29 (t, J = 8.0 Hz, 2H), 6.84 (s, 1H), 3.39 (s, 3H),2.07-1.98 (m, 1H), 1.01-0.96 (m, 2H), 0.83-0.79 (m, 2H); ESI-MS (m/z)439 (MH)⁺ Example-31: 2,6- Difluoro-N-(6-(5-methyl-3-(4-methyl-5-oxo-4,5- dihydro-1,3,4-oxadiazol- 2-yl)-1H-pyrazol-1-yl)pyridin-3- yl)benzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.29 (s, 1H, D₂O exchangeable), 8.80 (d, J =2.0 Hz, 1H), 8.39 (dd, J = 2.0 & 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H),7.68-7.6 (m, 1H), 7.30 (t, J = 8.0 Hz, 2H), 6.81 (s, 1H), 3.41 (s, 3H),2.62 (s, 3H); ESI-MS (m/z) 413 (MH)⁺ Example-32: 5-(1-(5-((2,6-Difluorobenzyl) amino)pyridin-2-yl)-5- methyl-1H-pyrazol-3-yl)-3-methyl-1,3,4- oxadiazol-2(3H)-one

¹HNMR (400 MHz, CDCl₃) 7.93 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.0 Hz,1H), 7.31-7.23 (m, 1H), 7.19 (dd, J = 2.0 & 8.0 Hz, 1H), 6.93 (t, J =8.0 Hz, 2H), 6.56 (s, 1H), 4.51 (d, J = 6.0 Hz, 2H), 4.31 (t, J = 6.0Hz, 1H, D₂O exchangeable), 3.50 (s, 3H), 2.58 (s, 3H); ESI-MS (m/z) 399(MH)⁺

Example-33(3-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazol-5-yl)methanol

To a stirred and cooled (0° C.) solution of Example-6 (30 mg, 0.061mmol) in methanol (3 mL) was added NaBH₄ (5 mg, 0.121 mmol). Theresulting mixture was warmed to room temperature and then stirred for 3h at the same temperature. Reaction was then diluted with water (3 mL)followed by ethyl acetate (5 mL). The layers were separated and theaqueous layer was extracted with ethyl acetate (2×5 mL). The combinedorganic layers were washed with brine (3 mL), dried (Na₂SO₄) andfiltered. The filtrate was rotary evaporated and the crude product waspurified by flash column chromatography (silica gel, ethylacetate-hexanes system as eluent) to afford 20 mg (70%) of the titlecompound as white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 7.93 (d, J=2.0 Hz,1H), 7.51 (d, J=8.0 Hz, 1H), 7.49-7.45 (m, 1H), 7.35 (s, 1H), 7.24 (dd,J=2.0 & 8.0 Hz, 1H), 7.18 (t, J=8.0 Hz, 2H), 6.82 (t, J=8.0 Hz, 1H),5.14 (t, J=5.0 Hz, 1H), 4.38 (d, J=5.0 Hz, 2H), 3.86-3.47 (m, 3H), 3.05(d, J=17.0 Hz, 1H), 1.32 (s, 3H); ESI-MS (m/z) 468 (MH)⁺

Example-34(3-(1-(5-((2-Chloro-6-fluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazol-5-yl)methanol

The title compound was prepared by following the similar procedure asdescribed in Example-33 using Example-7. ¹HNMR (400 MHz, CDCl₃) δ 7.99(d, J=2.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.30-7.23 (m, 2H), 7.21 (s,1H), 7.18 (dd, J=8.0 & 2.0 Hz, 1H), 7.07-7.02 (m, 1H), 4.57 (s, 2H),3.75 (d, J=12.0 Hz, 1H), 3.60 (d, J=12.0 Hz, 1H), 3.56 (d, J=17.0 Hz,1H), 3.16 (d, J=17.0 Hz, 1H), 1.44 (s, 3H); ESI-MS (m/z) 485, 487[(MH)⁺, Cl^(35,37)]

Example-35 Methyl3-(1-(5-(2,6-difluorobenzamido)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate

Step-1:2,6-Difluoro-N-(6-(3-formyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl) benzamide: In a sealed tube containing a dioxane (20 mL) andcesium carbonate (2.54 g, 7.81 mmol) was purged with nitrogen gas for 10min and then1-(5-bromopyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carbaldehyde(prepared in step-1 of the intermediate-12; 1.0 g, 3.12 mmol),2,6-difluorobenzamide (736 mg, 4.69 mmol) and xanthphos (180 mg, 0.31mmol) were sequentially added. The resulting mixture was thoroughlydeoxygenated by purging nitrogen gas for another 15 min and thenpalladium (II) acetate (35 mg, 0.15 mmol) was added to the abovemixture. The sealed tube was capped and stirred at 130° C. for 6 h. Thereaction mixture was then cooled to room temperature and filteredthrough celite. The filtrate was rotary evaporated and the crude productwas purified by flash column chromatography (silica gel, ethylacetate-hexanes system as eluent) to afford 700 mg (56%) of the titlecompound as white solid. ¹HNMR (400 MHz, CDCl₃) δ 10.09 (s, 1H), 8.63(d, J=2.0 Hz, 1H), 8.60 (dd, J=2.0 & 8.0 Hz, 1H), 8.00 (brs, 1H, D₂OExchangeable), 7.93 (d, J=8.0 Hz, 1H), 7.59-7.53 (m, 1H), 7.36 (s, 1H),7.09 (t, J=8.0 Hz, 2H); ESI-MS (m/z) 397 (MH)⁺

Step-2: 2,6-Difluoro-N-(6-(3-((hydroxyimino)methyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide:To (0° C.) cooled solution of the above Step-1 intermediate (900 mg,2.27 mmol) in methanol (10 mL) was added solution of hydroxylaminehydrochloride (237 mg, 3.41 mmol) in water (5 mL) followed by a solutionof sodium carbonate (241 mg, 2.27 mmol) in water (2 mL). The resultingmixture was then stirred at room temperature for 2 h. The reaction wasthen diluted with water (20 mL) followed by ethyl acetate (50 mL). Thelayers were separated and the aqueous layer was extracted with ethylacetate (2×50 mL). The combined organic layers were washed with brine(25 mL), dried (Na₂SO₄) and filtered. The filtrate was concentratedunder vacuum to afford 900 mg (96%) of the desired product as whitesolid. ESI-MS (m/z) 412 (MH)⁺

Step-3: Methyl3-(1-(5-(2,6-difluorobenzamido)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate:To a stirred solution of the above Step-2 intermediate (900 mg, 2.18mmol) in THF (25 mL) were added NCS (438 mg, 3.28 mmol) and pyridine(124 μL, 1.53 mmol) at 0° C. and then stirred at 45° C. for 2 h. Thereaction was cooled to 0° C., methyl methacrylate (350 μL, 3.28 mmol)was then added to the above mixture followed by triethyl amine (610 μL,4.38 mmol). The resulting mixture was stirred at 40° C. for 4 h. Thereaction was then cooled down to room temperature and diluted with water(50 mL) followed by ethyl acetate (25 mL). The layers were separated andthe aqueous layer was extracted with ethyl acetate (2×25 mL). Thecombined organic layers were washed with brine (20 mL), dried (Na₂SO₄)and filtered. The filtrate was rotary evaporated and the crude productwas purified by flash column chromatography (silica gel, ethylacetate-hexanes system as eluent) to afford 660 mg, (59%) of the titlecompound as white solid. ¹HNMR (400 MHz, DMSO) δ 11.37 (s, 1H, D₂Oexchangeable), 8.79 (d, J=2.0 Hz, 1H), 8.44 (dd, J=2.0 & 8.0 Hz, 1H),7.92 (d, J=8.0 Hz, 1H), 7.69-7.62 (m, 1H), 7.56 (s, 1H), 7.33 (t, J=8.0Hz, 2H), 3.90 (d, J=17.0 Hz, 1H), 3.72 (s, 3H), 3.51 (d, J=17.0 Hz, 1H),1.62 (s, 3H). ESI-MS (m/z) 510 (MH)⁺

Example-362,6-Difluoro-N-(6-(3-(5-(hydroxymethyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide

The title compound was prepared from Example-35 by following the similarprocedure as described in Example-33. ¹HNMR (400 MHz, CDCl₃) δ 8.56 (m,1H), 8.54 (d, J=2.0 Hz, 1H), 7.85-7.83 (m, 2H), 7.54-7.47 (m, 1H), 7.29(s, 1H), 7.07 (t, J=8.0 Hz, 2H), 3.79 (d, J=12.0 Hz, 1H), 3.36 (d,J=12.0 Hz, 1H), 3.61 (d, J=17.0 Hz, 1H), 3.20 (d, J=17.0 Hz, 1H), 1.47(s, 3H); ESI-MS (m/z) 482 (MH)+

Example-373-(1-(5-(2,6-Difluorobenzamido)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxamide

To a solution of from Example-35 (100 mg, 0.19 mmol) in methanol wasadded a solution of ammonia in methanol (5 mL) and the resultingsolution was heated to 100° C. and further maintained for 16 h. Thereaction was cooled to room temperature and the solvent was evaporatedunder reduced pressure. The crude product was triturated with 10% ethylacetate in hexane (10 mL) to afford 50 mg (50%) of the title compound aswhite solid. ¹HNMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 8.00 (d, J=2.0Hz, 1H), 8.44-8.41 (dd, J=2.0 & 8.0 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H),7.69-7.65 (m, 1H), 7.64 (brs, 1H, D₂O exchangeable), 7.54 (s, 1H), 7.44(brs, 1H, D₂O exchangeable), 7.33-7.29 (t, J=8.0 Hz, 2H), 3.81 (d,J=17.0 Hz, 1H), 3.37 (d, J=17.0 Hz, 1H), 1.58 (s, 3H); ESI-MS (m/z) 495(MH)⁺

Example-382,6-Difluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide

To a stirred solution of Intermediate-18 (75 mg, 0.230 mmol) in DCM (2mL) was added 2,6-difluorobenzoyl chloride (29 μL, 0.230 mmol), pyridine(37 μL, 0.460 mmol) followed by DMAP (5.62 mg, 0.046 mmol). Afterstirring the above reaction mixture at room temperature for 16 h, thereaction was diluted with DCM (10 mL), washed with aqueous hydrochloricacid (10%, 10 mL) brine (10 mL), dried (Na₂SO₄) and filtered. Thefiltrate was evaporated and the crude product was purified by flashcolumn chromatography to afford 25 mg (20%) of the desired product aswhite solid. ¹HNMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H, D₂O exchangeable),8.66 (d, J=2.5 Hz, 1H), 8.40 (d, J=8.5 Hz, 1H), 8.20 (dd, J=2.5 & 8.5Hz, 1H), 7.77 (s, 1H), 7.65-7.57 (m, 1H), 7.25 (t, J=8.5 Hz, 2H), 3.43(s, 3H); ESI-MS (m/z) 467 (MH)+.

The below Examples 39 to 50 given in Table-3 were prepared by followingthe similar procedure as described in Example-38 by usingIntermediate-18 and appropriate acid chloride.

TABLE 3 Example No: IUPAC name Structure ¹H-NMR/ESI-MS Example-39: 2-Chloro-6-fluoro-N-(5- (3-(4-methyl-5-oxo- 4,5-dihydro-1,3,4-oxadiazol-2-yl)-5- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2-yl)benzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1H, D₂O exchangeable), 8.66 (d, J =2.5 Hz, 1H), 8.42 (d, J = 8.5 Hz, 1H), 8.20 (dd, J = 2.5 & 8.5 Hz, 1H),7.78 (s, 1H), 7.59-7.54 (m, 1H), 7.45 (d, J = 7.5 Hz, 1H), 7.39 (t, J =7.5 Hz, 1H), 3.43 (s, 3H); ESI-MS (m/z) 483, 485 [(MH)⁺, Cl^(35,37)].Example-40: 2-Fluoro- 6-methyl-N-(5-(3-(4- methyl-5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2- yl)benzamide

¹HNMR (400 MHz, DMSO-d₆) δ 10.63 (s, 1H, D₂O exchangeable), 9.13 (d, J =2.5 Hz, 1H), 8.65 (dd, J = 2.5 & 8.5 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H),7.82 (s, 1H), 7.50-7.42 (m, 3H), 3.45 (s, 3H); ESI- MS (m/z) 483 (MH)⁺.Example-41: 2-Fluoro- N-(5-(3-(4-methyl-5- oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2-yl)benzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.32 (s, 1H, D₂O exchangeable), 8.66 (d, J =2.0 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.19 (dd, J = 2.0 & 8.0 Hz, 1H),7.78 (s, 1H), 7.76-7.72 (m, 1H), 7.65-7.59 (m, 1H), 7.39- 7.32 (m, 2H),3.43 (s, 3H); ESI-MS (m/z) 449 (MH)⁺ Example-42: 2,3-Difluoro-N-(5-(3-(4- methyl-5-oxo-4,5- dihydro-1,3,4- oxadiazol-2-yl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2- yl)benzamide

¹HNMR (400 MHz, CDCl₃) δ 9.19 (d, J = 12.0 Hz, 1H), 8.61 (d, J = 12.0Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 7.96-7.92 (m, 2H), 7.46-7.43 (m, 1H),7.33-7.28 (m, 2H), 3.55 (s, 3H); ESI-MS (m/z) 467 (MH)⁺ Example-43:2,4,5- Trifluoro-N-(5-(3-(4- methyl-5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)-5- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2-yl)benzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.45 (s, 1H, D₂O exchangeable), 8.67 (d, J =2.0 Hz, 1H), 8.39 (d, J = 8.0 Hz, 1H), 8.20 (dd, J= 2.0 & 8.0 Hz, 1H),7.95-7.89 (m, 1H), 7.80-7.73 (m, 1H), 7.78 (s, 1H) 3.43 (s, 3H); ESI-MS(m/z) 485 (MH)⁺ Example-44: 2,3,4- Trifluoro-N-(5-(3-(4-methyl-5-oxo-4,5- dihydro-1,3,4- oxadiazol-2-yl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2- yl)benzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.51 (s, 1H, D₂O exchangeable), 8.68 (d, J =2.0 Hz, 1H), 8.39 (d, J = 8.0 Hz, 1H), 8.20 (dd, J = 2.0 & 8.0 Hz, 1H),7.79 (s, 1H), 7.67-7.60 (m, 1H), 7.52-7.42 (m, 1H), 3.43 (s, 3H); ESI-MS(m/z) 485 (MH)⁺ Example-45: 2,4- Difluoro-N-(5-(3-(4- methyl-5-oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)-5- (trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2- yl)benzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.34 (s, 1H, D₂O exchangeable), 8.65 (d, J =2.0 Hz, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.18 (dd, J = 2.0 & 8.0 Hz, 1H),7.85-7.80 (m, 1H), 7.78 (s, 1H), 7.47-7.44 (m, 1H), 7.27-7.24 (m, 1H),3.43 (s, 3H); ESI-MS (m/z) 467 (MH)⁺ Example-46; 2,3-Dimethyl-N-(5-(3-(4- methyl-5-oxo-4,5- dihydro-1,3,4- oxadiazol-2-yl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2- yl)benzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.25 (s, 1H, D₂O exchangeable), 8.62 (d, J =2.0 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.16 (dd, J = 2.0 & 8.0 Hz, 1H),7.78 (s, 1H), 7.33-7.29 (m, 2H), 7.21-7.18 (m, 1H), 3.44 (s, 3H), 2.30(s, 3H), 2.28 (s, 3H); ESI-MS (m/z) 459 (MH)⁺ Example-47: 2-Chloro-N-(5-(3-(4- methyl-5-oxo-4,5- dihydro-1,3,4- oxadiazol-2-yl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2- yl)benzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.50 (s, 1H, D₂O exchangeable), 8.64 (d, J =2.0 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.18 (dd, J = 2.0 & 8.0 Hz, 1H),7.78 (s, 1H), 7.65 (dd, J = 2.0 & 7.0 Hz, 1H), 7.58-7.56 (m, 1H),7.54-7.50 (m, 1H), 7.48- 7.44 (m, 1H), 3.43 (s, 3H); ESI-MS (m/z) 465,467 [(MH)⁺, Cl^(35,37)] Example-48: 2- Methyl-N-(5-(3-(4-methyl-5-oxo-4,5- dihydro-1,3,4- oxadiazol-2-yl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2- yl)benzamide

¹HNMR (400 MHz, DMSO-d₆) δ 11.24 (s, 1H, D₂O exchangeable), 8.63 (d, J =2.0 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.16 (dd, J = 2.0 & 8.0 Hz, 1H),7.77 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.43-7.39 (m, 1H), 7.32-7.28 (m,2H), 3.43 (s, 3H), 2.42 (s, 3H); ESI-MS (m/z) 445 (MH)⁺ Example-49:4-Ethyl- N-(5-(3-(4-methyl-5- oxo-4,5-dihydro-1,3,4- oxadiazol-2-yl)-5-(trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2- yl)benzamide

¹HNMR (400 MHz, CDCl₃) δ 8.81 (s, 1H, D₂O exchangeable), 8.62 (d, J =8.0 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 7.93 (dd, J = 2.0 & 8.0 Hz, 1H),7.89 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.27 (s, 1H), 3.55(s, 3H), 2.76 (q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H); ESI- MS(m/z) 459 (MH)⁺ Example-50: N-(5-(3- (4-Methyl-5-oxo-4,5- dihydro-1,3,4-oxadiazol-2-yl)-5- (trifluoromethyl)-1H- pyrazol-1-yl)pyridin-2-yl)-2-naphthamide

¹HNMR (400 MHz, CDCl₃) δ 8.96 (s, 1H, D₂O exchangeable), 8.68 (d, J =8.0 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.51-8.50 (m, 1H), 8.03-8.01 (m,4H), 7.98-7.94 (m, 2H), 7.68- 7.60 (m, 2H), 3.56 (s, 3H); ESI-MS (m/z)481 (MH)⁺

Example-515-(1-(6-((2,6-Difluorobenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one

To a stirred solution of Intermediate-18 (100 mg, 0.307 mmol) inmethanol (5 mL), containing molecular sieves (100 mg), was added 2,6-difluorobenzaldehyde (97 mg, 0.61 mmol) and acetic acid (35 μL, 0.61mmol). The reaction was stirred at room temperature for 18 h. Sodiumcyanoborohydride (38.5 mg, 0.613 mmol) was then added to the abovemixture. The resulting mixture was stirred at room temperature for 18 hand then filtered. The solid obtained was washed with methanol andpurified by preparative HPLC to obtain 80 mg (55%) of the title compoundas white solid. ¹HNMR (400 MHz, CDCl₃) δ 8.22 (d, J=2.5 Hz, 1H), 7.57(dd, J=2.5 & 8.5 Hz, 1H), 7.33-7.25 (m, 1H), 7.20 (s, 1H), 6.92 (t,J=7.5 Hz, 2H), 6.63 (d, J=8.5 Hz, 1H), 5.57 (s, 1H), 4.68 (d, J=6.5 Hz,2H), 3.53 (s, 3H); ESI-MS (m/z) 453 (MH)+.

Example-525-(1-(6-((2-Chloro-6-fluorobenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one

The title compound was prepared by following the similar reductiveamination procedure as described in Example-51 using Intermediate-18 and2-chloro-6-fluorobenzaldehyde. ¹HNMR (400 MHz, DMSO-d₆) δ 8.20 (d, J=2.5Hz, 1H), 7.64 (s, 1H), 7.59 (dd, J=2.5 & 8.5 Hz, 1H), 7.50-7.48 (m, 1H),7.46-7.37 (m, 1H), 7.39 (s, 1H), 7.26-7.22 (m, 1H), 6.66 (d, J=8.5 Hz,1H), 4.63 (s, 2H), 3.42 (s, 3H); ESI-MS (m/z) 469, 471 [(MH)⁺,Cl^(35,37)]

Example-535-(1-(6-((2-Fluoro-6-methylbenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one

The title compound was prepared by following the similar reductiveamination procedure as described in Example-51 using Intermediate-18 and2-fluoro-6-methylbenzaldehyde. ¹HNMR (400 MHz, CDCl₃) δ 8.24 (d, J=2.5Hz, 1H), 7.50 (dd, J=2.5 & 8.5 Hz, 1H), 7.23-7.17 (m, 1H), 7.20 (s, 1H),7.02 (d, J=7.0 Hz, 1H), 6.96 (t, J=7.0 Hz, 1H), 6.50 (d, J=8.5 Hz, 1H),4.88 (s, 1H), 4.64 (s, 2H), 3.53 (s, 3H), 2.46 (s, 3H); ESI-MS (m/z) 449(MH)⁺

Example-54N-(2,6-Difluorophenyl)-6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinamide

A stirred suspension of Intermediate-3 (0.40 g, 1.12 mmol) and SOCl₂(3.29 mL, 45.0 mmol) was heated to 90° C. and maintained for 4 h. Excessof SOCl₂ was evaporated. The residue was azeotroped with toluene anddissolved in DCM (20 mL) and 2,6-difluoroaniline (160 mg, 1.23 mmol),pyridine (0.273 mL, 3.38 mmol) and DMAP (0.014 g, 0.113 mmol) weresequentially added at 0° C. to the above solution. The reaction was thenwarmed to room temperature and then stirred for 18 h at the sametemperature. Reaction was cooled back down to 0° C. and ice water (10mL) was added. The separated solid was filtered and dried under vacuumto afford 70 mg (13%) of the desired product as a white solid. ¹HNMR(400 MHz, DMSO-d₆) δ 10.58 (s, 1H, D₂O exchangeable), 9.13 (d, J=2.5 Hz,1H), 8.65 (dd, J=2.5 & 8.5 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.82 (s,1H), 7.50-7.42 (m, 1H), 7.24 (t, J=8.0 Hz, 2H), 3.45 (s, 3H); ESI-MS(m/z) 467 (MH)⁺.

Example-55 N-(2-Chloro-6-fluorophenyl)-6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinamide

The title compound was prepared by reacting Intermediate-3 with2-chloro-6-fluoroaniline, by following the similar procedure asdescribed in Example-54. ¹H NMR (400 MHz, DMSO-d₆) δ 10.63 (s, 1H, D₂Oexchangeable), 9.13 (d, J=2.5 Hz, 1H), 8.65 (dd, J=2.5 & 8.5 Hz, 1H),8.15 (d, J=8.5 Hz, 1H), 7.82 (s, 1H), 7.50-7.42 (m, 3H), 3.45 (s, 3H);ESI-MS(m/z) 483 (MH)⁺.

Biological Assays and Utility:

The CRAC channel modulatory activity of the compounds were thusevaluated by measuring the secretion of IL-2 by antigen stimulatedT-cells in vitro. Alternatively, such activity can also be evaluated byassay methods known to one skilled in the art.

In Vitro Assay Example-56

Inhibition of IL-2 secretion: Jurkat T cells were seeded at a density of0.5 to 1 million cells per well in RPMI medium. Test compounds from thisinvention were added to the cells at different concentrations. This wasfollowed by the addition of PHA, a T cell mitogen after 10 minutes. Thecells were then incubated for 20 to 24 hours in a CO₂ incubator at 37°C. After incubation with the compounds, cells were centrifuged, thesupernatant was collected and processed for ELISA to quantitate theamount of IL-2 secreted. A commercial ELISA kit (R&D Systems, Inc.Minneapolis, Minn., USA) was used to estimate the IL-2 concentrations.Amount of IL-2 secreted by cells stimulated with PHA was considered as a100% maximal signal and the decrease in amount of IL-2 secreted by cellstreated with the test compounds was expressed as percent inhibition ofthe maximal signal. The dose response data was analyzed using4-parametric sigmoidal dose response (variable slope) curve-fit.

In the above IL-2 assay, compounds of the invention were found to haveIC₅₀ (nM) values as shown below:

IC₅₀ (nM) Examples  <100 nM 8, 9, 10, 11. 12, 14, 15, 18, 22, 23, 32,33, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 51, 52, 53, 55100 nM-1000 nM 1, 2, 3, 5, 6, 7,16, 17, 19, 20, 21, 24, 25, 34, 35 26,27, 28, 29, 30, 49, 50, 54 >1000 nM 4, 13, 31

Thus, compounds of the invention are shown to inhibit IL-2 secretion.

Example-57

SOCE inhibition: Jurkat E6.1 cells were seeded at a density of 1-2×10⁵cells per well in calcium-4 dye prepared in calcium free HBSS (Sigma,USA). Test compounds from this invention were added to the cells atdifferent concentrations. This was followed by the addition ofthapsigargin (TG), a SERCA inhibitor, to empty the stores of calcium.Calcium chloride was added to the cells after 10-30 min to inducecalcium influx and the fluorescence was measured for 10 min using theFLIPR-Tetra detection system. Fluorescence was also measured using aplate reader at 485 nm excitation and 520 nm emission (Synergy2, Biotek,USA) after 30-90 minutes of calcium addition. Fluorescence observed incells treated with Thapsigargin and calcium chloride solution wasconsidered 100% maximal signal and the reduced fluorescent signalobserved in the presence of test compounds was expressed as percentageinhibition of the maximal signal. The dose response data was analysedusing 4-parametric sigmoidal dose response (variable slope) curve-fit.

In the above SOCE inhibition assay, compounds of the present inventionshowed activity less than <1000 nM against SOCE. Thus, compounds of theinvention are shown to have CRAC channel modulation activity byinhibition of SOCE.

Example-58

NFAT Transcriptional Activity: HEK 293 cells were stably co-transfectedwith a NFAT-FireflyLuciferase and Tk-Renilla Luciferase reporter genes30,000-80,000 cells were seeded per well. Test compounds from thisinvention were added to the cells at different concentrations.Thapsigargin (TG) was added after 10 minutes and the cells wereincubated for 4-8 h. The NFAT-Firefly luciferase and Tk-Renillaluciferase activity was measured using Dual-Glo reagent (Promega USA).The Renilla luciferase activity was used for protein normalization.Luminescence observed in cells treated with thapsigargin was considered100% maximal signal and the reduced fluorescent signal observed in thepresence of test compounds was expressed as percent inhibition of themaximal signal. The data was analyzed using 4-parametric sigmoidal doseresponse (variable slope) curve-fit.

In the above NFAT transcriptional activity assay, compounds of thepresent invention showed activity less than <1000 nM. Thus, compounds ofthe invention are shown to inhibit NFAT transcription activity.

Thus, the in vitro screening assays showed that the compounds ofinvention inhibit CRAC channel activity.

As mentioned hereinbefore, the CRAC channel is involved with numerousbiological responses through various Ca²⁺ signaling pathways. Thecompounds of the present invention are therefore useful for thetreatment and/or prophylaxis of, although not limited to, inflammatoryconditions, cancer, rheumatoid arthritis, allergic disorders, immunedisorders, cardiovascular diseases, thrombocytopathies and all relatedconditions which can be benefitted by the CRAC channel modulatoryproperties of the compounds described herein.

The compounds of the present invention can be administered to awarm-blooded animal, including human being, for the treatment and/orprophylaxis of one or many diseases or disorders mentioned hereinabovewhich can be benefitted by the CRAC channel modulatory properties of thecompounds described herein. The compounds may be formulated according tothe methods known in the art as well as by new methods and may beadministered to the body system via gastro-intestinal tract as well asvia other routes known to a person skilled in the art. Thus,administration of the compounds of the present invention via oral route,parenteral route, inhalation and/or topical applications are within thescope of this application. Any combination of a compound of the presentinvention with excipients and/or other therapeutic agents known in theart for the said conditions, diseases and/or disorders are alsoencompassed by the present invention.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

Although certain embodiments and examples have been described in detailabove, those having ordinary skill in the art will clearly understandthat many modifications are possible in the embodiments and exampleswithout departing from the teachings thereof. All such modifications areintended to be encompassed within the below claims of the invention.

1. A compound having the Formula (I):

wherein, one of A and B is N and the other is CR₃; L is selected from—C(O)NR₁₁—, —CR_(a)R_(b)NR₁₁— and —NR₁₁CR_(a)R_(b)—; at each occurrence,R_(a) and R_(b) are independently hydrogen, substituted or unsubstitutedalkyl or halogen; ring E is 5 membered non aromatic heterocyclic ringselected from Formula (a) to (c)

at each occurrence, X is selected from —C(O)—, —CR₄R₅— and —NR—; at eachoccurrence, Y is —C(O)— or —CR₄R₅—; provided that both of X and Y arenot simultaneously —C(O)—; R is selected from substituted orunsubstituted alkyl, substituted or unsubstituted haloalkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocyclyl, —C(O)NR₆R₇,—C(O)OR₉ and —C(O)R₈; R₁, which may be same or different at eachoccurrence, is independently selected from halogen, cyano, nitro,hydroxyl, substituted or unsubstituted alkyl, substituted orunsubstituted haloalkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted haloalkoxy, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkoxy, —NR₆R₇, —NHC(O)R₈,and —C(O)OR₉; or any two of adjacent R₁ groups together with the phenylto which they are attached form substituted or unsubstituted naphthalenering; R₂ is selected from halogen, cyano, nitro, hydroxyl, substitutedor unsubstituted alkyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedhaloalkoxy, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkoxy, —NR₆R₇, —NHC(O)R₈, and —C(O)OR₉; R₃ isselected from hydrogen, halogen, cyano, nitro, hydroxyl, substituted orunsubstituted alkyl, substituted or unsubstituted haloalkyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted haloalkoxy,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkoxy, —NR₆R₇, —NHC(O)R₈, and —C(O)OR₉; R₄ and R₅, which may besame or different at each occurrence, are independently selected fromhydrogen, halogen, —OR₁₀, substituted or unsubstituted alkyl,substituted or unsubstituted haloalkyl, substituted or unsubstitutedhydroxyalkyl, —C(O)OR₉, —C(O)—NR₆R₇, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstituted heterocyclyl;provided that, when any of R₄ or R₅ in Y is —OR₁₀ then R₁₀ is nothydrogen; R₆ and R₇, which may be same or different at each occurrence,are independently selected from hydrogen, substituted or unsubstitutedalkyl and substituted or unsubstituted cycloalkyl; or R₆ and R₇,together with the nitrogen atom to which they are attached, may form asubstituted or unsubstituted, saturated or unsaturated 3 to 12 memberedcyclic ring, wherein the unsaturated cyclic ring may have one or twodouble bonds; R₈, which may be same or different at each occurrence, isindependently selected from substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedcycloalkyl, and substituted or unsubstituted aryl; R₉, which may be sameor different at each occurrence, is independently selected fromhydrogen, substituted or unsubstituted alkyl and substituted orunsubstituted aryl; R₁₀ is selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl and substituted or unsubstituted heterocyclyl; at eachoccurrence, R₁₁ is independently hydrogen or substituted orunsubstituted alkyl; and n is an integer ranging from 0 to 4, bothinclusive; or a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1, having the Formula (II):

or a pharmaceutically acceptable salt thereof; wherein ring E, R₁, R₂,R₃, L and ‘n’ are as defined in claim-1.
 3. The compound of claim 1,having the Formula-(III):

or a pharmaceutically acceptable salt thereof; wherein ring E, R₁, R₂,R₃, L and ‘n’ are as defined in claim-1.
 4. The compound of claim 1,wherein ring E is selected from (a) to (c)

wherein R, X and Y as defined in claim-1, and or a pharmaceuticallyacceptable salt thereof.
 5. The compound of claim 1, wherein L isselected from —C(O)NR₁₁—, —NR₁₁C(O)— and —NR₁₁CR_(a)R_(b)— wherein R₁₁,R_(a) and R_(b) are independently a hydrogen or substituted orunsubstituted alkyl.
 6. The compound of claim 1, wherein R₁ is same ordifferent and are independently selected from halogen, cyano, nitro,hydroxyl, substituted or unsubstituted alkyl, substituted orunsubstituted haloalkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted haloalkoxy and substituted or unsubstitutedcycloalkyl; and ‘n’ is 0, 1, 2, or
 3. 7. The compound of claim 1,wherein R₂ is selected from halogen, hydroxyl, cyano, nitro, substitutedor unsubstituted alkyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedhaloalkoxy and substituted or unsubstituted cycloalkyl.
 8. The compoundof claim 1, wherein R₃ is selected from hydrogen, halogen, cyano, nitro,hydroxyl, substituted or unsubstituted alkyl, substituted orunsubstituted haloalkyl, substituted or unsubstituted alkoxy andsubstituted or unsubstituted cycloalkyl.
 9. The compound of claim 1,wherein one of A and B is N and the other is CH; L is —C(O)NH—, —NHC(O)—or —NHCH₂—; R₁ is same or different and are independently selected fromhalogen, substituted or unsubstituted alkyl, substituted orunsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; ‘n’is 0, 1, 2, or 3; R₂ is halogen, substituted or unsubstituted alkyl,substituted or unsubstituted haloalkyl or substituted or unsubstitutedcycloalkyl; R₃ is selected from hydrogen, halogen or substituted orunsubstituted alkyl; and ring E is selected from


10. The compound of claim 1, which is selected from:2,6-Difluoro-N-(6-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;2-Fluoro-6-methyl-N-(6-(5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;5-(3-Cyclopropyl-1-(5-((2,6-difluorobenzyl)amino)pyridin-2-yl)-1H-pyrazol-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;N-(6-(3-(Difluoromethyl)-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(fluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;Methyl3-(1-(5-((2,6-difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate;Methyl3-(1-(5-((2-chloro-6-fluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate;2,6-Difluoro-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;2-Chloro-6-fluoro-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;2-Fluoro-6-methyl-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;N-(6-(5-(Difluoromethyl)-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(difluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-3-(difluoromethyl)-1H-pyrazol-5-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;N-(6-(3-(5,5-Dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;2-Chloro-N-(6-(3-(5,5-dimethyl-4-oxo-4,5-dihydroisoxazol-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-6-fluorobenzamide;2,6-Difluoro-N-(6-(1′,4′,4′-trimethyl-5′-oxo-5-(trifluoromethyl)-4′,5′-dihydro-1H,1′H-[3,3′-bipyrazol]-1-yl)pyridin-3-yl)benzamide;2-Chloro-6-fluoro-N-(6-(1′,4′,4′-trimethyl-5′-oxo-5-(trifluoromethyl)-4′,5′-dihydro-1H,1′H-[3,3′-bipyrazol]-1-yl)pyridin-3-yl)benzamide;2-Fluoro-6-methyl-N-(6-(1′,4′,4′-trimethyl-5′-oxo-5-(trifluoromethyl)-4′,5′-dihydro-1H,1′H-[3,3′-bipyrazol]-1-yl)pyridin-3-yl)benzamide;2,6-Difluoro-N-(6-(3-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;N-(6-(3-(4-Acetyl-5,5-dimethyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;N-(6-(3-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;5-(1-(5-((2-Chloro-6-fluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;1′-(5-(2,6-Difluorobenzyl)amino)pyridin-2-yl)-1,4,4-trimethyl-5′-(trifluoromethyl)-1H,1′H-[3,3′-bipyrazol]-5(4H)-one;1′-(5-((2-Chloro-6-fluorobenzyl)amino)pyridin-2-yl)-1,4,4-trimethyl-5(trifluoromethyl)-1H, 1′H-[3,3′-bipyrazol]-5(4H)-one;3-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-methyl-1,2,4-oxadiazol-5(4H)-one;1-(5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,2-dimethyl-1,3,4-oxadiazol-3(2H)-yl)ethanone;N-(2,6-Difluorobenzyl)-6-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-amine;N-(6-(5-Cyclopropyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;N-(6-(3-Cyclopropyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)-2,6-difluorobenzamide;2,6-Difluoro-N-(6-(5-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;5-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-methyl-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;(3-(1-(5-((2,6-Difluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazol-5-yl)methanol;(3-(1-(5-((2-Chloro-6-fluorobenzyl)amino)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazol-5-yl)methanol;Methyl3-(1-(5-(2,6-difluorobenzamido)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate;2,6-Difluoro-N-(6-(3-(5-(hydroxymethyl)-5-methyl-4,5-dihydroisoxazol-3-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzamide;3-(1-(5-(2,6-Difluorobenzamido)pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-methyl-4,5-dihydroisoxazole-5-carboxamide; 2,6-Difluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;2-Chloro-6-fluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;2-Fluoro-6-methyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;2-Fluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;2,3-Difluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;2,4,5-Trifluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;2,3,4-Trifluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;2,4-Difluoro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;2,3-Dimethyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;2-Chloro-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;2-Methyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;4-Ethyl-N-(5-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)benzamide;N-(5-(3-(4-Methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-2-yl)-2-naphthamide;5-(1-(6-((2,6-Difluorobenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;5-(1-(6-((2-Chloro-6-fluorobenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;5-(1-(6-((2-Fluoro-6-methylbenzyl)amino)pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-3-methyl-1,3,4-oxadiazol-2(3H)-one;N-(2,6-Difluorophenyl)-6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinamideandN-(2-Chloro-6-fluorophenyl)-6-(3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinamideor pharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition comprising one or more compounds of Formula (I) according toclaim 1 and one or more pharmaceutically acceptable excipients.
 12. Amethod of treating, managing and/or lessening diseases or disorders,syndromes or conditions associated with the modulation of calciumrelease-activated calcium (CRAC) channel in a subject in need thereofwherein the method comprises administering to the subject atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 13. The method of claim 12,wherein the diseases, disorders, syndromes or conditions associated withthe modulation of calcium release-activated calcium (CRAC) channel areselected from the group consisting of inflammatory diseases, autoimmunediseases, allergic disorders, organ transplant, cancer andcardiovascular disorders.
 14. The method of claim 12, wherein thedisease is rheumatoid arthritis, multiple sclerosis and psoriasis. 15.The method of claim 12, wherein the disease is allergic disordersselected from asthma, chronic obstructive pulmonary disorder (COPD) orrespiratory disorders.
 16. The method of claim 13, wherein inflammatorydiseases are selected from rheumatoid arthritis, osteoarthritis,ankylosing spondylitis, psoriatic arthritis, chronic obstructivepulmonary disease (COPD), inflammatory bowel diseases, pancreatitis,peripheral neuropathy, multiple sclerosis (MS) and inflammationassociated with cancer.
 17. A process for the preparation of a compoundof Formula (IIa):

wherein L is —NR₁₁C(O)— or NR₁₁CR_(a)R_(b); ring E, A, B, R_(a), R_(b),R₁, R₂, R₃, R₁₁ and ‘n’ are as described herein above; the processcomprising the steps: a) oxidizing a compound of Formula (10) where X ishalogen, NO₂, COOR′ where R′ is H, alkyl etc., by using suitableoxidation agents to give compound of Formula (11) in suitablesolvent(s);

b) converting a acid compound of Formula (11) to cyclized compound ofcompound of Formula (12) by following acid ester formation thenheterocyclic ring formation using hydrazine hydrate followed bytriphosgene

c) coupling of compound Formula (12) where X′ is halogen, with compoundof Formula (6) where L′ is C(O) or CR_(a)R_(b) where R_(a), R_(b) andR₁₁ are hydrogen or alkyl, to give compound of Formula (IIa) by usingsuitable reagents and suitable solvent.


18. The process for the preparation of compound claim 17, having theFormula (IIa):

wherein L is —NR₁₁C(O)— or NR₁₁CR_(a)R_(b); ring E, A, B, R_(a), R_(b),R₁, R₂, R₃, R₁₁ and ‘n’ are as described herein above; the processcomprising the steps: a) reducing a nitro group in compound of Formula(12) where X′ is NO₂, by using suitable reducing agent to give aminocompound of Formula (13) where R₁₁ is hydrogen, in suitable solvent

b) coupling of compound of Formula (13) with compound of Formula (8) byusing suitable amide coupling reagents or suitable reductive amidationreagents to give compound of Formula (IIa)


19. A process for the preparation of a compound of Formula (IIb):

wherein ring E, A, B, R₁, R₂, R₃, R₁₁ and ‘n’ are as described hereinabove; amide coupling of compound Formula (12) where X′ is COOR′ whereR′ is H, alkyl etc., with compound of Formula (5a) to give compound ofFormula (IIb) by using suitable amide coupling methods